Software resources in drug design

P R E S E N T E D B Y :
SURMIL SHAH
2 N D S E M E S T E R M . P H A R M
SOFTWARE RESOURCES

CONTENT
 KEY WORDS
 MOLECULAR MECHANICS(MM3 &MM4)
 HUCKEL-MO-CALCULATOR
 MOPAC (semi-empirical)
 GAUSSIAN(Ab initio)
 SciQSAR
 PDB
 SYBYL
 CHARMM
 HyperChem
 MM+
 AMBER
 MOE
 DISCOVERY STUDIO
 FlexX
 GOLD
 SCHRODINGER
 Chem3D
 ALCHEMY 2000

KEY WORDS
• CNDO - Complete Neglect of Differential Overlap: spherically
symmetric orbitals only
• INDO - Intermediate Neglect of Differential Overlap: one
centre repulsion integrals between orbitals on the same
atom.
• MINDO - Modified Intermediate Neglect of Differential
Overlap: empirical data to parameterize the repulsion
integrals rather than analytic solutions
• NDDO - Neglect of Diatomic Differential Overlap: includes
directionality of orbitals on the same atom for repulsion
integrals
• MNDO - Modified Neglect of Differential Overlap: better
determination for multi-centre repulsion integrals

MOLECULAR MECHANICS (MM3 AND MM4)
(A) MM3
 Bonds, angles and torsions are not independent in
molecules.
 They couple with one another.
 Cross terms between all contributions in a force field
should be considered, especially when calculating
vibrational frequencies.
 Most cross terms involve two internal coordinates
such as stretch-stretch, bend-bend, stretch-bend,
stretch torsion, etc.

 Some force fields (MM2, MM3) include cross terms
involving three or more internal coordinates, for
example stretch-stretch-bend.
 Based on QM calculations Dinur and Hagler (1991)
proposed the most important terms to be: stretch-
stretch, stretch-bend, bend-bend, stretch-torsion
and bend-bend-torsion.

Popular cross terms expressions
 Ustr−str = 1 2 kab,bc(rab − rab,0)(rbc − rbc,0)
 Ubend−bend = 1 2 kabc,dbe(θabc − θabc,0)(θdbe −
θdbe,0)
 Ustr−bend = 1 2 kab,abc(rab − rab,0)(θabc − θabc,0)
 Ustr−tors = 1 2 kbc,abcd (rbc − rbc,0)(1 + cos(nφ −
ψ))

CROSS TERMS
 Presence of cross terms can characterize force fields.
 Class I - harmonic potential with no cross terms.
 Class II - includes cross terms and and harmonic
terms. Class II force fields aim at reproducing not
only geometry but also vibrational frequencies.
 Class III - accounts for electronegativity,
polarizability or hyperconjugation.
 By adding extra terms to a potential energy
expression one obtains a more accurate force field.
More parameters will better match the experimental
data. Parameterization of more parameters is more
complicated and time consuming.

(B) MM4
 MM4 is the latest in the well-known series of molecular
mechanics programs developed by Prof. N. L. Allinger
and co-workers at the University of Georgia.
 The high quality geometries and energies generated by
these applications have led to their widespread
recognition as the industry standard for calculating small
molecule structures.
 MM4 continues this trend, offering increased accuracy in
calculating molecular structures, performing
conformational analyses, and computing spectroscopic
and thermodynamic properties.

 Structures calculated by quantum mechanics differ from those
measured experimentally because of the vibrational motions of
the molecules. Newer methods have been developed in MM4 that
permit a more accurate interconversion of these types of
structures.
 The enlarged parameter set available in MM4 extends its
capabilities to more classes of small molecules encountered in
pharmaceutical or agrochemical research programs.
 MM4 can carry out calculations on coordination compounds,
including square planar for four coordinate; trigonal bipyramid
and square pyramid for five coordinate; and octahedral
bipyramid for six coordinate compounds. Conjugated p-systems
are analyzed by a Variable Electronegativity SelfConsistent Field
(VESCF) calculation to determine bond orders and lengths both
initially and throughout optimization of the surrounding
structure.

 MM4's treatment of hydrogen bonding is improved
through the use of special van der Waals distances and a
directional character in the hydrogen bonding function
that accurately accounts for its anisotropic nature. Other
specialized intramolecular interactions, such as the
anomeric and trans lone-pair (Bohlmann) effect are
reproduced accurately.
 MM4 considers not only charge-charge, charge-dipole,
and dipole-dipole interactions, but also calculates dipole-
induced dipoles. These are important in molecules
containing many highly polar groups, such as peptides
and polyols. Unlike other force fields, the MM4 charge
distribution on each atom depends on the conformation
since each conformation has different induced dipoles.

Huckel-MO-calculator
 SHMO (Simple Hückel Molecular Orbital Calculator)
 SHMO is an interactive program to perform electronic structure
calculations within the "Simple Hückel Molecular Orbital"
approximations. The theoretical basis for the method is
described in "Orbital Interaction Theory of Organic Chemistry",
Second Edition by Arvi Rauk (Wiley Interscience, 2001),
Chapters 3 and 5.
 SHMO is designed as a teaching aid and replaces the earlier
version distributed with the book. Besides performing
conventional SHMO calculations, SHMO permits easy changes of
orbital electronegativities (the Hückel coulomb integrals, alpha,
hX) and intrinsic orbital interaction values (the Hückel
resonance integrals, beta, kXY) to illustrate the effects of
interacting orbital energies orbital, energy differences and
overlaps on the resultant molecular orbital energies and
polarizations.

 The first version of this program has been written entirely in
the Java language by Richard Cannings. Some bug fixes and
new options, and new display of the data and the molecular
orbitals has been programmed by Hans-Ulrich Wagner.
 Orbitals are displayed as red/green or light grey/grey
coloured circles. Empty oribtals can be displayed with white
centers, half filled with yellow centers. This option can be
switched using the button "Occup".
 Orbital energies are displayed as "alpha + x beta" (the
coulomb integral, alpha, and the resonance integral, beta, are
both negative).
 Orbital selection is by clicking on the orbital energy display or
step up/step down buttons.

 Heteroatoms, X, are incorporated as aX = alpha + hX beta,
and bXY = kXY beta , where the default values of the
parameters, hX and kXY, are taken from the publication of
F. A. Van-Catledge, J. Org. Chem. 1980, 45, 4801-4802.
 Structural formula can be drawn in Hückel which
serves as input to the calculation. From the structure
formula, Hückel builds the matrices involved and
performs the calculations. The resulting energy levels
are presented in a level diagram, and a molecular
orbital diagram shows the resulting molecular
orbitals.

 Advanced users will appreciate that Hückel provides
access to all the results of the calculations involved.
They may be readily output to the printer and/or
copied to the Windows clipboard if desired. The
number of atoms used in the calculations is virtually
unlimited. The speed of the calculation will depend
on the size of the molecule and on speed of your PC.
With a 133 Mhz Pentium it takes about 45 seconds to
calculate a molecule with 75 atoms. Hückel permits
task switching during the calculations.

 The atoms available in the structure formula editor
are defined in a database. This database may be
easily modified for custom applications. By allowing
the definition of new atoms, the parameters involved
in the Hückel calculations can be changed.

Software resources in drug design

MOPAC
 The name MOPAC should be understood to mean
"Molecular Orbital PACkage".
 The origin of the name is unique, and might be of
general interest: The original program was written in
Austin, Texas. One of the roads in Austin is unusual
in that the Missouri-Pacific railway runs down the
middle of the road. Since this railway was called the
MO-PAC, when names for the program were being
considered, MOPAC was an obvious contender.

MOPAC
 MOPAC is a general-purpose semiempirical molecular
orbital package for the study of solid state and molecular
structures and reactions.
 The semiempirical Hamiltonians MNDO , AM1, PM3,
PM6,RM1, MNDO-d , and PM7 are used in the electronic
part of the calculation to obtain molecular orbitals, the
heat of formation and its derivative with respect to
molecular geometry.
 Using these results MOPAC calculates the vibrational
spectra, thermodynamic quantities, isotopic substitution
effects and force constants for molecules, radicals, ions,
and polymers.
 For studying chemical reactions, a transition state
location routine and two transition state optimizing
routines are available.

MOPAC
 While MOPAC calls upon many concepts in quantum theory
and thermodynamics and uses some fairly advanced
mathematics, the user need not be familiar with these
specialized topics.
 MOPAC is written with the non-theoretician in mind. The
input data are kept as simple as possible, so users can give
their attention to the chemistry involved and not concern
themselves with quantum and thermodynamic exotica.
 The simplest description of how MOPAC works is that the
user creates a data-file which describes a molecular system
and specifies what kind of calculations and output are desired.
 The user then commands MOPAC to carry out the calculation
using that data-file. Finally, the user extracts the desired
output on the system from the output files created by MOPAC.

GAUSSIAN
 Gaussian 09 is the latest version of the Gaussian® series
of electronic structure programs, used by chemists,
chemical engineers, biochemists, physicists and other
scientists worldwide.
 Starting from the fundamental laws of quantum
mechanics, Gaussian 09 predicts the energies, molecular
structures, vibrational frequencies and molecular
properties of molecules and reactions in a wide variety of
chemical environments.
 Gaussian 09’s models can be applied to both stable
species and compounds which are difficult or impossible
to observe experimentally (e.g., short-lived intermediates
and transition structures).

GAUSSIAN
A) Comprehensive Investigations of Molecules and
Reactions
 With Gaussian 09, you can thoroughly investigate the chemical
problems that interest you. For example, not only can you
minimize molecular structures rapidly and reliably, you can
also predict the structures of transition states, and verify that
the located stationary points are in fact minima and transition
states.
 You can go on to compute the reaction path by following the
intrinsic reaction coordinate (IRC) and determine which
reactants and products are connected by a given transition
structure. Once you have a complete picture of the potential
energy surface, reaction energies and barriers can be accurately
predicted.

GAUSSIAN
B) Predicting and Interpreting Spectra
 Spectroscopy is a fundamental tool for investigating molecular structures
and properties. However, observed spectra are often difficult to interpret.
The results of electronic structure calculations can be vital to this process.
For example, predicted spectra can be examined in order to determine peak
assignments in observed spectra as well as comparing peak locations and
intensities with experimental data. Gaussian 09 can also compute relevant
spectroscopic constants and related molecular properties with excellent
accuracy.
 Gaussian 09 can predict a variety of spectra including IR and Raman,
NMR, UV/Visible, Vibrational circular dichroism (VCD), Raman optical
activity (ROA), Electronic circular dichroism (ECD), Optical rotary
dispersion (ORD), Hyperfine spectra (microwave spectroscopy), Franck-
Condon, Herzberg-Teller and Franck-Condon/Herzberg-Teller analyses.

SciQSAR
SciQSAR 2D provides powerful, 2D molecular descriptors for QSAR/QSPR
analysis on compound databases SciQSAR 2D is packed with integrated
features to make over 600 of these powerful descriptors easily accessible,
no matter whether you're working with one molecule or thousands!
 It interfaces alchemy 2000 and Chem3D.
Molecular Descriptors
 Molecular connectivity
 Molecular shape
 Topological
 Electrotopological (Atom E & H E-States)
 Electrotopological bond types

SciQSAR
Reads 2D/3D Structure Input
 Smiles and SLN strings
 ISIS SKC
 Alchemy AL2, Hin, MDL Mol, Mol2, SDF
 Use built-in 2D sketcher

SciQSAR
Data Collection
 Menu-driven selection of descriptors
 Automated processing
 Ability to use only pharmacophoric atoms
 Ability to renumber atoms "on-the-fly"
 See descriptor values at-a-glance
 Output selected descriptors to Microsoft Excel

PDB
 The Protein Data Bank (PDB) is a repository for the
three-dimensional structural data of large biological
molecules, such as proteins and nucleic acids.
 The data, typically obtained by X-ray
crystallography or NMR spectroscopy and submitted
by biologists and biochemists from around the world, are
freely accessible on the Internet via the websites of its
member organisations (PDBe, PDBj, and RCSHB).
 The PDB is overseen by an organization called
theWorldwide Protein Data Bank, wwPDB.

PDB
 The PDB is a key resource in areas of structural biology,
such as structural genomics.
 Most major scientific journals, and some funding
agencies, now require scientists to submit their structure
data to the PDB. If the contents of the PDB are thought of
as primary data, then there are hundreds of derived (i.e.,
secondary) databases that categorize the data differently.
For example, both SCOP and CATH categorize structures
according to type of structure and assumed evolutionary
relations; GO categorize structures based on genes.[4]

PDB
 Most structures are determined by X-ray diffraction, but
about 10% of structures are now determined by protein
NMR.
 When using X-ray diffraction, approximations of the
coordinates of the atoms of the protein are obtained,
whereas estimations of the distances between pairs of
atoms of the protein are found through NMR
experiments.
 Therefore, the final conformation of the protein is
obtained, in the latter case, by solving a distance
geometry problem. A few proteins are determined
by cryo-electron microscopy.

SYBYL
 It is a tool developed by Certara(Tripos) for molecular
modeling and simulation.
 SYBYL-X’s science offers unique, competitive advantages
in a number of key areas vital for today’s successful
discovery research, which are summarized below:
• 3D QSAR: use the power of industry leading CoMFA
in a new way to generate novel ideas for R-groups —
predict the level of biological activity or potency based on
structure-activity data, not just yes/no activity
predictions
• Ligand-based virtual screening: search millions
of compounds overnight — don’t miss hits because you
only screened subsetted portions of your database

SYBYL
 Cheminformatics: produce highly focused queries
that avoid false positives using rich set of 3D queries;
on-the fly conformational searching means you only
store a single conformation of your molecules,
keeping database size small and very transportable
• Docking: custom tailor and fine-tune docking to a
particular receptor site using information like SAR or
known poses to improve rank ordering of ligands

SYBYL
SYBYL‐X Suite includes the following :
 Core technologies
1. SYBYL‐X Base
2. Concord Sketch
3. MOLCAD
 Advanced Computation Pharmacophore Perception
4. GALAHAD
5. Tuplets
6. GASP
7. DISCOtech
8. Distill
 QSAR Technologies
10. QSAR with CoMFA
11. Advanced CoMFA
12. HQSAR
13. cLogP/CMR

SYBYL
 Protein Modeling & Structure Prediction
14. Biopolymer
15. Advanced Protein Modeling
16. Virtual Screening/Docking
17. Surflex‐Dock
18. Cscore
 Virtual Screening/ R‐groups
19. Topomer CoMFA
20. Topomer Search Combinatorial Chemistry
21CombiLibMaker/Legion*
22. DiverseSolutions*
23. Selector

SYBYL
 ChemInformatics
23. UNITY Base & 3D
24. Concord Standalone**
25. StereoPlex*
 Value Added Tools
26. Confort
27. ProtoPlex**
28. Surflex‐Si

SYBYL
 SAR and QSAR
Certara (then Tripos) was an early pioneer in QSAR (in particular 3D QSAR),
and continues to build on that tradition of scientific innovation with key
QSAR techniques explicitly designed to advance Lead Optimization:
Comparative Molecular Field Analysis (CoMFA) was the first 3D
QSAR method, and is an industry standard with literally thousands of
literature publications demonstrating CoMFA’s utility for molecular
discovery. With CoMFA, researchers build statistical and graphical models
that relate the chemical and biological properties of molecules to their 3D
structures and the 3D steric and electrostatic properties. These models are
then used to predict the properties or activity of novel compounds.
Hologram QSAR (HQSAR) is a novel 2D QSAR method, and uses counts
of key molecular substructures and PLS to generate fragment-based
structure-activity relationships. Validation studies have shown that
HQSAR has predictive capabilities comparable to those of much more
complicated 3D-QSAR techniques.

SYBYL
With Topomer CoMFA, the next generation of CoMFA/3D
QSAR, Certara is revolutionizing 3D QSAR all over
again. Building on the innovation originated in the
traditional CoMFA method, Topomer CoMFA minimizes the
preparation needed for 3D QSAR analysis. These models can
be created in minutes, and can easily be used by both QSAR
experts and QSAR non-experts. Because pose generation is
automated with Topomer CoMFA, researchers can:
 Easily generate models for multiple biological endpoints
 Identify novel ideas for R-groups that are most likely to lead
to improvements in activity using virtual screening based on
predictions from 3D QSAR models
 Generate 100’s to 1000’s of predictive QSAR models for
chemogenomic studies automatically by mining large
databases of chemical and biological data

SYBYL
 Ligand Based Virtual Screening and Shape Based
Similarity and Alignment, Pharmacophore Searching
The SYBYL-X Suite includes a comprehensive set of tools for shape
and pharmacophore based analysis and virtual screening:
 Topomer Search is an exceptionally fast 3D ligand-based virtual
screening tool that has been demonstrated to be effective for both lead
hopping and scaffold hopping.
 Topomer Search can search millions of structures overnight on a single
processor, allowing you to screen very large collections of compounds
and avoid the risk of missing important leads because of subsetting.
Screen for whole molecules, side chains, or scaffolds using
conformationally independent topomer similarity.

SYBYL
 Surflex-Sim performs rigorous, flexible 3D shape based virtual
screening. In addition, the molecular alignments and hypotheses of
bioactive ligand conformations generated by Surflex-Sim stimulate
3-D ligand-based design. Surflex-Sim's comprehensive shape
comparison algorithms include the consideration of the molecules’
shape, H-bonding, and electrostatic properties. Shape similarity, as
computed by Surflex-Sim has been shown to be highly effective as
means of rationalizing and predicting both on- and off-target
pharmacological effects.
 UNITY-3D is an industry standard with literally thousands of
literature publications demonstrating successful lead discovery
based on UNITY's conformationally flexible pharmacophore based
searching. UNITY's rich set of pharmacophore features enable
highly specific queries to be constructed from a lead structure, a
pharmacophore model, or a receptor active site.

SYBYL
 Galahad, GASP, and DiscoTech are pharmacophore
hypothesis generation tools that deduce the spatial
requirements for drug binding when a structure of the
drug’s target isn’t known. The pharmacophore models that
are generated are useful for virtual screening and for
inspiring and testing new ideas to see how they match to a
set of lead drug candidates

SYBYL
Structure Based Design
The SYBYL-X Suite includes :
 Surflex-Dock™ offers unparalleled enrichments in virtual high-
throughput screening and accurate prediction for ligand binding
mode and conformation.
 Surflex-Dock has been extensively validated and favorably
compared to all leading competing methods by independent
researchers along with numerous studies by the application's
author, Prof. Ajay N. Jain, Ph.D., a faculty member at the University
of California San Francisco Cancer Research Institute. Its unique
capabilities allow users to customize scoring functions, consider
protein flexibility, multiple binding site detection and docking, and
key fragment constraints and make Surflex-Dock a top choice for
lead discovery, scaffold replacement, lead optimization and
fragment based discovery.

SYBYL
 Advanced Protein Modeling (APM) for protein homology
modeling enables you to perform both homolog finding and
comparative modeling through a streamlined interface. APM finds
more relevant homologs to start the modeling process because in
takes advantage of environment-specific substitution tables,
structure-dependent gap penalties, automated alignment method
selection, and the highly annotated HOMSTRAD database.
 Homologs are structurally aligned based using homology and local
structural environment, and then structurally conserved regions are
identified using backbone curvature and torsion in addition to C-
alpha rmsd and homology.
 Loops (structurally variable regions) are then modeled by
knowledge-based or ab initio approaches, and sidechains are added
by enumerating rotamer combinations constrained by borrowing as
much information from the parent homologs as possible. A range of
analysis tools are available to highlight potential problems with the
structure and allow the user to iterate through the process and
refine initial models.

SYBYL
 MOLCAD exploits the power of the human eye by
creating graphical images that reveal the properties of
molecules essential for molecular recognition. MOLCAD
calculates and displays the surfaces of both small
molecule drugs and macromolecular targets and can
identify channels and cavities that may be potential
binding sites. A broad range of properties can be
mapped onto these surfaces to rationalize the properties
of the binding site and ligand/receptor complementarity.

CHARMM force field
 CHARMM (Chemistry at HARvard Macromolecular Mechanics) is the
name of a widely used set of force fields for molecular dynamics as well
as the name for the molecular dynamics simulation and
analysis package associated with them.
 The CHARMM force fields for proteins include:
 united-atom (sometimes called "extended atom") CHARMM19,all-
atom CHARMM22 and its dihedral potential corrected variant
CHARMM22/CMAP.
 In the CHARMM22 protein force field, the atomic partial charges
were derived from quantum chemical calculations of the interactions
between model compounds and water. Furthermore, CHARMM22 is
parametrized for the TIP3P explicit water model.
 Nevertheless, it is frequently used with implicit solvents. In 2006, a
special version of CHARMM22/CMAP was reparametrized for
consistent use with implicit solvent GBSW.

CHARMM force field
 For DNA, RNA, and lipids, CHARMM27 is used. Some
force fields may be combined, for example CHARMM22
and CHARMM27 for the simulation of protein-DNA
binding. Additionally, parameters for NAD+, sugars,
fluorinated compounds, etc. may be downloaded.
 These force field version numbers refer to the CHARMM
version where they first appeared, but may of course be
used with subsequent versions of the CHARMM
executable program. Likewise, these force fields may be
used within other molecular dynamics programs that
support them.

CHARMM force field
 In 2009, a general force field for drug-like molecules
(CGenFF) was introduced. It "covers a wide range of
chemical groups present in biomolecules and drug-like
molecules, including a large number of heterocyclic
scaffolds".
 The general force field is designed to cover any
combination of chemical groups. This inevitably comes
with a decrease in accuracy for representing any
particular subclass of molecules.
 Users are repeatedly warned in Mackerell's website not
to use the CGenFF parameters for molecules for which
specialized force fields already exist (as mentioned above
for proteins, nucleic acids, etc.).

HYPERCHEM
 HyperChem is a sophisticated molecular modeling
environment that is known for its quality, flexibility,
and ease of use.
 Uniting 3D visualization and animation with
quantum chemical calculations, molecular
mechanics and dynamics, HyperChem puts more
molecular modeling tools at your fingertips than any
other Windows program.
 It includes all the components of structure,
thermodynamics, spectra, and kinetics.

HYPERCHEM
Display
 Rendering choices: Ball-and-stick, fused CPK spheres,
ball and cylinders, or tubes with optional shading and
highlighting. Also vdW dots added to any rendering.
 Ribbon rendering for protein backbones, with optional
sidechain display.
 Cylinders, ribbon lines, thin solid ribbons, thick ribbons
and coils for secondary structure rendering.
 3D Isosurfaces or 2D contour plots of: Total charge
density.
 Molecular orbitals, Spin density, Electrostatic potential
(ESP).

HYPERCHEM
 ESP mapped onto 3D charge density surface
 Isosurface rendering choices: wire mesh, JorgensenSalem,
transparent and solid surfaces, Gouraud shaded surface.
User-specified grid and isosurface value.
 Generate ray-traced graphical images.
 During simulations, display and average kinetic, potential,
and total energy, as well as values of user-specified bond
lengths, bond angles, or torsion angles.
 Spectra display of IR or UV-VIS. Animate vibrational modes.
 NMR spectra.
 Crystal structures.
 Slides (molecules plus annotations).

HYPERCHEM
Predict
 Relative stabilities of isomers
 Heats of formation
 Activation energies
 Atomic charges
 HOMO-LUMO energy gap
 Ionization potentials
 Electron affinities
 Dipole moments
 Electronic energy levels
 MP2 electron correlation energy
 CI excited state energy

HYPERCHEM
 Transition state structures and properties
 Non-bonded interaction energy
 UV-VIS absorption spectra
 IR absorption spectra
 Rate constants - unimolecular or bimolecular reactions
 Equilibrium as a function of temperaure
 Isotope effects on vibrations
 Collision effects on structural properties
 Stability of clusters
 Shielding and coupling constant
 s Conformations of flexible systems
 Homologous proteins

HyperChem
Save Results
 Use Import/Export option to save results of
quantum mechanics calculations or to view results
generated by other programs.
 Use HyperChem Data to store structures and
properties in a custom molecular database.
 Create Reaction Movies in AVI format

MM+
 Merck Molecular Force Field (MMFF) is a family
of force fields developed by Merck Research
Laboratories.
 They are based on the MM3 force field. MMFF is not
optimized for a single use (like either simulating
proteins or small molecules), but tries to perform
well for a wide range of organic chemistry
calculations. The parameters in the force field have
been derived from computational data.
 The first published force field in the family is
MMFF94.

MM+
 Screening of tens of thousands of compounds based on
pharamcophoric models or “interactions” with the
binding site of a target molecule. Accordingly,
parameters for a wide variety of chemicals are required.
 Class I force fields have limited transferability, therefore
are only parameterized for a limited number of chemical
types and are of limited value for screening large
numbers of compounds.
 Class II force fields, with their greater transferability,
allow for a large number of compounds to be treated, as
required for database screening.

MM+
 MMFF: A Class II force field designed to be a
transferable force field for pharmaceutical
compounds that accurately treats conformational
energetics and nonbonded interactions. This would,
ideally, produce a force field that was adequate for
both gas phase and condensed phase calculations.
 Transferability: Application of empirical force field
parameters to molecules not explicitly included
during the parameter optimization.

AMBER
 AMBER (an acronym for Assisted Model Building with
Energy Refinement) is a family of force
fields for molecular dynamics of biomolecules originally
developed by Peter Kollman's group at the University of
California, San Francisco.
 AMBER is also the name for the molecular dynamics
software package that simulates these force fields.
 The term "AMBER force field" generally refers to the
functional form used by the family of AMBER force
fields. This form includes a number of parameters; each
member of the family of AMBER force fields provides
values for these parameters and has its own name.

AMBER
 The meanings of right hand side terms are:
 First term (summing over bonds): represents the energy between
covalently bonded atoms. This harmonic (ideal spring) force is a
good approximation near the equilibrium bond length, but becomes
increasingly poor as atoms separate.
 Second term (summing over angles): represents the energy due to
the geometry of electron orbitals involved in covalent bonding.
 Third term (summing over torsions): represents the energy for
twisting a bond due to bond order (e.g. double bonds) and
neighboring bonds or lone pairs of electrons. Note that a single
bond may have more than one of these terms, such that the total
torsional energy is expressed as a Fourier series.
 Fourth term (double summation over and ): represents the non-
bonded energy between all atom pairs, which can be decomposed
into van der Waals (first term of summation)
and electrostatic (second term of summation) energies.

AMBER
 To use the AMBER force field, it is necessary to have values for the
parameters of the force field (e.g. force constants, equilibrium bond
lengths and angles, charges). A fairly large number of these
parameter sets exist, and are described in detail in the AMBER
software user manual. Each parameter set has a name, and provides
parameters for certain types of molecules.
 Peptide, protein and nucleic acid parameters are provided by
parameter sets with names beginning with "ff" and containing a two
digit year number, for instance "ff99".
 GAFF (General AMBER force field) provides parameters for small
organic molecules to facilitate simulations of drugs and small
molecule ligands in conjunction with biomolecules.
 The GLYCAM force fields have been developed by Rob Woods for
simulating carbohydrates.

AMBER
The AMBER software suite provides a set of programs for applying the AMBER
forcefields to simulations of biomolecules. It is written in Fortran 90 and C with
support for most major Unix-like systems and compilers. Development is conducted
by a loose association of mostly academic labs. New versions are generally released
in the spring of even numbered years; AMBER 10 was released in April 2008. The
software is available under a site-license agreement, which includes full source,
currently priced at US$400 for non-commercial and US$20,000 for commercial
organizations.
Programs
 LEaP is used for preparing input files for the simulation programs
 Antechamber automates the process of parameterizing small organic molecules
using GAFF
 SANDER (Simulated Annealing with NMR-Derived Energy Restraints) is the
central simulation program and provides facilities for energy minimization and
molecular dynamics with a wide variety of options
 pmemd is a somewhat more feature-limited reimplementation of sander by Bob
Duke. It was designed with parallel processing in mind and has significantly better
performance than sander when running on more than 8–16 processors

AMBER
 pmemd.cuda has been made in order to run simulations on GPU enabled
machines
 pmemd.amoeba was developed to handle the extra parameters in the
polarizable AMOEBA force field.
 nmode calculates normal modes
 ptraj provides facilities for numerical analysis of simulation results.
AMBER does not include visualization capabilities; visualization is
commonly performed with VMD. Ptraj is now unsupported as of
AmberTools 13.
 cpptraj is a rewritten version of ptraj made in C++ to provide faster
analysis of simulation results. Several actions have been made
parallelizable with OpenMP and MPI
 MM-PBSA allows for implicit solvent calculations on snap shots from
molecular dynamics simulations
 NAB is a built in nucleic acid building environment made to aid in the
process of manipulating proteins and nucleic acids where an atomic level of
description will help with computation.

MOE
 MOE, the Molecular Operating Environment, is a comprehensive
software system for Life and Material Science developed by
Chemical Computing Group Inc. (CCG).
 MOE is a combined Applications Environment and Methodology
Development Platform that integrates visualization, simulation and
application development in one package.
 MOE strongly supports drug design through molecular simulation,
protein structure analysis, data processing of small molecules,
docking study of proteins and small molecules, and so on under the
unified operations.
 SVL, the Scientific Vector Language, is the portable high
performance programming language built-in MOE. SVL is the
vectrized command language, scripting language and applications
programming language.
 One-tenth reductions in code size over C and FORTRAN are
routinely realized. SVL source code to MOE applications is
distributed with MOE to end-users; this allows MOE applications to
be freely customized or modified.

MOE
Structure-Based Design
 Active Site Detection
 Protein:Ligand Interaction Diagrams
 Streamlined Interface for Ligand Optimization
 Contact Statistics, Electrostatic, and Interaction Maps
 Solvent Analysis with 3D-RISM
 Scaffold Replacement
 Ligand:Receptor Docking
 Multi-Fragment Search
 Automated Structure Preparation

MOE
Fragment-Based Design
 Scaffold Replacement
 Ligand Hybridization
 Fragment Linking and Growing
 Medicinal Chemistry Transformations
 Automatic Filtering and Scoring
 Fragment Databases
Pharmacophore Discovery
 Ligand- and Structure-Based Query Editor
 Automatic Pharmacophore Generation
 Conformation Databases
 Virtual Screening
 Ligand- and Structure-Based Scaffold Replacement

MOE
Medicinal Chemistry Applications
 Streamlined Interface for Structure-Based Ligand Optimization
 Visualize and Analyze Non-Bonded Interactions
 Protein-Ligand Interaction Diagrams
 Surfaces and Maps
 Conformational Search and Analysis
 Flexible Alignment of Multiple Molecules
 Scaffold Replacement, Growing and Fragment Linking
 Pharmacophore Discovery
 SAReport
 Molecular Descriptors for QSAR
 Virtual Library Builder

MOE
Biologics Applications
 Whole Protein and Interface Visualization and Analysis
 2D Protein Interaction Diagrams
 Mutation and Rotamer Exploration
 Sequence Analyzer and Editor
 Protein Engineering
 Antibody and Fusion Protein Modeler
 Protein Properties
 Advanced Molecular Simulations
Molecular Modeling and Simulations
 Molecular Mechanics
 Molecular Dynamics

MOE
 Conformational Search and Analysis
 Quantum Mechanical and Semi-Empirical Calculations
 Flexible Alignment of Multiple Molecules
Protein and Antibody Modeling
 Protein Structure Databases
 Remote Homology and Fold Identification
 Multiple Sequence/Structure Alignment and Analysis
 Mutation and Rotamer Exploration
 Protein and Antibody Structure Prediction
 Advanced Loop Conformation Generation
 Protein Geometry Quality Assessment

MOE
Cheminformatics and QSAR
 Powerful Database Viewer and Workflow Integration
 Import, Prepare, Filter, Sort, Merge and Export Molecular Data
 Combinatorial Library Design
 Molecular Descriptors
 QSAR and QSPR Modeling
 Similarity, Diversity, and Fingerprints
 SAReport

Methods Development and Deployment
 Platform Independent
 Scientific Vector Language

DISCOVERY STUDIO
 Discovery Studio® is a single unified, easy-to-use,
graphical interface for powerful drug design and protein
modeling research.
 Discovery Studio contains both established gold-
standard applications (e.g., Catalyst, MODELER,
CHARMm, etc.) with years of proven published results,
as well as and cutting-edge science to address today’s
drug discovery challenges.
 Discovery Studio is built on the SciTegic Pipeline Pilot
Scitegic Enterprise Server platform™ open operating
platform, allowing seamless integration of protein
modeling, pharmacophore analysis, and structure based
design, as well as third-party applications.

PLATFORMS
 Discovery Studio Standalone
 Discovery Studio Standalone is a complete molecular
modeling platform designed for the independent modeler.
 This standalone environment, powered by the Pipeline Pilot
open platform, includes the entire infrastructure needed to
design and run modeling experiments with Discovery Studio
Science.
 Easily visualize, model, and analyze biological and chemical
data using tools for sketching 3D molecules, visualizing
dynamic changes, 3D graphing and a host of other
functionality.
 The standalone installation can be connected to a Pipeline
Pilot Server for easy sharing of workfl ows and data. This confi
guration also includes access to a rich set of perl-based
scripting commands

PLATFORMS
 Discovery Studio Visualizer Client
 Discovery Studio Visualizer Client is a powerful graphical interface
to access Discovery Studio Science.
 DS Visualizer Clients can be inexpensively deployed and easily
maintained for research teams while still offering world-class
science.
 When deployed with a Pipeline Pilot Server, DS Visualizer Client
offers unparalleled capabilities for sharing data, workfl ows, and
computational resources.
 A rich set of perl-based scripting commands, and customized
scripts, are also available for the automation and customization of
common modeling operations that replicate UI actions or act on DS
data models.
 Some examples of the large collection of scriptable actions include
molecular overlay, chirality and valency checks, prediction of DSC
secondary structure, access to electrostatics tools, management of
constraints/restraints, and display of surfaces

PLATFORMS
 Pipeline Pilot Server
 Pipeline Pilot makes the most of your information
through industrial-scale data flow control and powerful
mining capabilities.
 You can graphically compose data processing networks,
using hundreds of different configurable components for
operations such as data retrieval, manipulation,
computational filtering, and display.
 These protocols are automatically captured as you create
them and you can even publish them for enterprise level
deployment.
 Your colleagues have the option to invoke your protocols
and run them using their own data using a simple Web
interface.

PLATFORMS
 DS Developer Client
 This scaled-down version of the Pipeline Pilot client allows you to
customize pre-existing Discovery Studio work flows, and also
includes the necessary component collections to enable
customization.
 Add or remove available components from existing DS protocols/
components. Create a new component and add to an existing DS
protocol. Increase automation of DS Protocols (e.g. automate DS
protocol to run over all files in a specific folder).
 Easily connect to an external relational database. Integrate third-
party algorithms (e.g., CORINA, proprietary codes for descriptor
calculations, etc.). The customized protocols can be run directly
from the DS Developer Client, or saved into a user area and run
from the DS interface for interactive modeling.
 A free and extensive library of customized components and
protocols for Discovery Studio is available at no additional cost at
the Accelrys Forums.

PLATFORMS
 Discovery Studio Free Visualizer
 This free, easy-to-use visualization tool is an ideal
solution for managers and researchers who need to
collaborate with modelers, but do not need access to the
expert-level analysis tools in Discovery Studio.
 Many common tasks and commands are available within
the Perlbased scripting API, enabling automation and
customization of common modeling tasks.
 View and share protein and small-molecule data in a
clear and consistent way, and in a wide variety of
industry-standard formats.

PLATFORMS
 ActiveX Control
 The Discovery Studio Visualizer ActiveX Control is a fully
integrated, 3D molecular renderer for the Windows
environment, and provides a powerful method of sharing
scientific results with colleagues via presentations, web
pages, etc.
 The Control can be inserted into any application that can
host a COM component, such as Internet Explorer,
PowerPoint, or VC clients.
 The OpenGL capabilities of ActiveX Control allow you to
render sophisticated molecular images.
 In addition to the Viewer’s native format, the ActiveX
Control can read many industry standard molecular fi le
formats.

Applications
 Protein Modeling and Sequence Analysis
 Biopolymer Building and Analysis
 Simulations
 Structure-Based Design
 Ligand-Based Design
 Pharmacophore Modeling and Analysis
 QSAR and Library Design
 ADMET

FlexX
 FlexX is a computer program for predicting protein-ligand interactions.
 For a given protein and a ligand, FlexX predicts the geometry of the
complex as well as an estimate for the strength of binding. In this first
version of FlexX, the protein is assumed to be rigid.
 Thus, the protein must be given in a conformation which is similar to the
bound state. The docking algorithm in FlexX works without manual
intervention. Nevertheless, in some cases additional information about the
ligand or even the complex is known.
 You can integrate this knowledge in the computations with FlexX by
performing single steps manually.
 Thus, FlexX is ideal for interactive work on protein-ligand complexes as
well as for screening a larger set of ligands in order to find new leads for
drug design.
 In summary, FlexX can be useful in the following situation: You have a
good three-dimensional model of the protein and you know the location of
the active site. You have a set of ligands and you want to know whether and
how each of them binds to your protein model.

FlexX
 Major workflows with FlexX is:
1. Preparation of the binding site using the Receptor Intelligence of the
Receptor Preparation Wizard This includes selection of chains,
receptor protonation, tautomers, etc.
2. Optional: Definition of a receptor-based pharmacophore
3. Read in of a ligand “Docking Library” (one or more ligands)
4. Docking including possibly altering of parameters and further
cycles of docking
 The character of this workflow is driven by few ligands and/or a
preparational stage. It can easily and comfortably be accomplished
with LeadIT .
 A Receptor, once prepared with the Wizard, can be saved and read
into the commandline mode of FlexX.
 Precondition: You must have one or more ligands in a low-energy
conformation ready to dock. FlexX does not minimize ligands
before docking. The docking process deals with the translational,
torsional, and ring conformation degrees of freedom only.

FlexX
Scientifically, FlexX is currently further developed at three
locations, at BioSolveIT GmbH (Sankt Augustin), at the ZBH
of the University of Hamburg (Hamburg) and at the Max-
Planck-Institute for Computer Science (Saarbrücken).
Current further developments of the software:
 FlexX-PVM: Automatic scheduling on large compute clusters
 FlexX-C: Efficient docking of combinatorial libraries
 FlexX-PHARM: Docking under pharmacophore peripheral
conditions
 FlexX-Ensemble (FlexE): Docking in consideration to protein
flexibility
 FlexX-Scan: Fast Structure-Based Virtual Screening using a
novel receptor binding site descriptor
 FlexX Metal Interaction: Automatic calculation and definition
of metal coordination geometries

Introduction to CCDC GOLD Suite
• CCDC- Cambridge Crystallographic Data
Centre
• GOLD (Genetic Optimisation for Ligand Docking) is
a genetic algorithm for docking flexible ligands
into protein binding sites.
• Predicting how a small molecule will bind to a
protein is difficult, and no program can
guarantee success. The next best thing is to measure
as accurately as possible the reliability of the
program, i.e. the chance that it will make a successful
prediction in a given instance.

GOLD
• GOLD is supplied as part of the GOLD Suite, which
includes two additional software component, Hermes
and GoldMine.
The Hermes visualiser can be used to assist the
preparation of input files for docking with GOLD,
visualisation of docking results and calculation
of descriptors. The Hermes visualiser is also used for
interactive docking setup, e.g. for defining the binding
site and the setting of constraints.
GoldMine is a tool for the analysis and post-
processing of docking results

Using the GOLD Wizard to Prepare the
Protein File
 Selecting a Protein
In the Select proteins to use window, read in the
protein file, 3S7S.pdb, by hitting
the Load Protein button,
Select the file
Click on Open.

STEPS
 Add hydrogens: All hydrogen atoms must be present in the protein input
file The hydrogen atoms are placed on the protein in order to ensure that
ionisation and tautomeric states are defined unambiguously. Advanced
options within GOLD allow for switching between different tautomeric
states during docking.
 Delete Waters: Water molecules often play key roles in protein-ligand
recognition. Water molecules can either form mediating hydrogen bonds
between protein and ligand, or be displaced by the ligand on binding.
Water molecules within the active site can be retained and allowed to toggle
(i.e. switch on and off during docking) and rotate to optimise their H-
bonding positions. Those outside of the binding site can be removed from
the protein altogether.
 Delete ligands The 3S7S.pdb protein is the raw PDB file which is the
original protein-ligand complex. For GOLD to effectively dock a ligand back
into the active site, the co-crystallised ligand must first be removed.

Defining the Protein Binding Site
 It is necessary to specify the approximate centre and
extent of the protein binding site, this can be done in
a number of ways from within the Define the binding
site window, including from :
A protein atom
A point
A reference ligand
A file containing a list of atoms or residues

Specifying a Configuration File Template
 At this point you are given the option to load a
configuration file template. Configuration templates
can be used to load recommended settings for a
number of different types of docking protocols
 Click Next to proceed to the Select ligands step.

Specifying the Ligand File
From within the Select Ligands window it is possible
to Add single ligands
Select a complete directory of ligand files.
Specify a single file containing several ligands (i.e.
a multi-MOL2 or SD file).
Click Next to proceed to the Choose a fitness
function window.

Selecting a Fitness Function
 GOLD offers a choice of scoring functions
GoldScore
ChemScore
Astex Statistical Potential
CHEMPLP
User Defined Score

Selecting Docking Speed
 GOLD optimises the fitness score using a genetic
algorithm (GA).
 A number of parameters control the precise operation of
the genetic algorithm. The settings are encapsulated into
three speeds:
 Slow (most accurate): this equates to 100,000
operations
 Medium: 50,000 operations
 Fast (least accurate): 10,000 operations

STEPS
 Finished our docking setup and re presented with a Run
GOLD button with which we can start the docking.
 If we were to click on Run GOLD now, the output would
be written to the directory the 3S7S.pdb file is stored in. It
is generally preferable to write output to a separate
directory.

LIGANDS
 PDB ID: 3S7S
Ligands taken
OO2N
NH
S O
O
OO2N
N
S O
O
CH3
O
CH3
O2N
N
S OO
CH3
O
CH3
O2N
NH
S OO
OO2N
NH
S OO
OO2N
N
S
O
O
CH3
O
O2N
HN S
O
O
OO2N
N
S
O
O
CH3
Mol 01 Mol 02 Mol 03 Mol 04
Mol 05 Mol 06 Mol 07
Mol 08

SCHRODINGER
 Schrödinger software suite is a drug design software using both
ligand and structure-based methods. Schrödinger provides accurate,
reliable, and high performance computational technology to solve
real-world problems in life science research. It provides superior
solutions and services for the design, selection, and optimization of
novel drug candidates.
 Schrödinger's predictive models will enable drug discovery
scientists to assess properties of chemical compounds early in the
discovery process and to select drug candidates that have optimal
profiles.
 The predictive power of Schrödinger's software allows scientists to
accelerate their research and development activities, reduce
research costs, and make novel discoveries that might not be
possible with other computational or experimental approaches.
 Maestro is a powerful, all-purpose molecular modeling
environment. Maestro is the unified interface for all
Schrödinger software products.

MODULES
 Phase
 Maestro
 MarcModel
 Prime
 Jaguar
 Glide
 Liaison
 Qsite
 Impact

 Phase- pharmacophore generation module.
 Maestro- Schrodinger modelling interface.
 Macro modeller- basic molecular modelling
package (build/ edit functions, minimization and
dynamics).
 Prime- protein homology modeller (secondary
structure prediction combined with homology
modelling).
 Jaguar- ab initio modelling software (quantum
mechanical calculations for small molecules).
 Glide- ligand docking program (drug screening).
 Liason- ligand binding affinity software.
 Qsite- combined quantum mechanics/ molecular
modelling package (investigation of enzyme active
sites).

Glide
 Glide is designed to assist in high-throughput screening
of potential ligands based on binding mode and affinity
for a given receptor module.
 One can compare ligand scores with those of other test
ligands or compare ligand geometrics with those of a
reference ligand.
 Additionally one can use Glide to generate one or more
plausible binding modes for a newly designed ligand.
 Once favourable structures and/or bonding
conformations are located with Glide one may use
Liaison to obtain binding energies for ligand-receptor
pairs.

liasion
 Liaison is designed to predict ligand binding
energies.
 Ligands for which binding energies are known are
used to calculate the Liaison SVD-fitted parameters-
alpha, beta, and gamma.
 These parameters are subsequently used to predict
binding energies for other ligands with the same
receptor.

QSite
 QSite is mixed mode Quantum Mechanics/Molecular
Mechanics program to study geometries and
energies of structures not parameterized for use with
molecular mechanics, such as those that contain
metals or transition states.
 Qsite is uniquely equipped to perform QM/MM
calculations because it combines the superior speed
and power of Jaguar.

Maestro
 Maestro is the graphical user interaface for all
Schrödinger's products.
 FirstDiscover (Glide, Impact, Liaison and Qsite)
Jaguar, MacroModel etc.
 It contains tools for building, displaying, and
manipulating chemical structures, for organizing,
loading and storing these structures and associated
data and for setting up, monitoring, and visualizing
the results of calculations on these structures.

Impact
 Impact is the computational engine that can perform
molecular mechanics calculations either through the
maestro interface or from the command line

Jaguar
 Jaguar is designed to increase the speed of ab initio
calculations in order to accelerate basic and applied
research projects and to enable calculations at a
higher level of theory.
 Jaguar's speed and power make it possible to study
larger systems than ever before, or to study many
more systems than previously possible, within a
reasonable time frame.

MarcModel
 MarcModel, with a large selection of force fields and
advanced methods for conformational analysis,
molecular dynamics, and free energy calculations, is
the most trusted name in molecular mechanics.
 MarcModel is especially well suited for general-
purpose molecular mechanics for small and
medium-sized organic molecules in both gas and
solution phases.
 Further, MarcModel has powerful utilities for
exploring proteins and protein-ligand complexes.

PRIME
 Prime is highly accurate protein structure prediction
suite of programs that integrates comparative
modelling and fold recognition into a single user
friendly, wizard like interface.
 Prime SP (Structure Prediction) consists of a series of
steps leading from a protein sequence through
comparative modelling to the construction of a 3D
structure.

CHEM3D
 Chem3D is a molecular modeling package.
 It performs calculations using MM2 and extended
Huckel as well as acting graphic interface for MOPAC or
GAUSSIAN.
 There are also plug-ins available for viewing structures
and surfaces.
 Integrated with molecular analysis, this modeling,
visualization and analysis suite provides simultaneous 2-
D and 3-D editing, automatic display of hydrogen bonds
in the 3-D view, graphical display distance and angle
measurements in the 3-D view that are linked to the
measurements table, and the ability to compute
electronic properties with MOPAC, GAMESS, Gaussian
and Jaguar.

Creating, Opening, and Importing Models
 Chem3D provides the following starting points for
modeling:
Creating a model using the Chem3D tools
Opening an existing 3D model
Creating a model from stationery or templates
Importing files in other chemistry file formats

MM2 in Chem3D
 The Chem3D MM2 menu provides computations using
the MM2 force field.
 The MM2 procedures described assume that you
understand how the potential energy surface relates to
conformations of your model.
 The energy minimization routine performs a local
minimization only. Therefore, the results of minimization
may vary depending on the starting conformation in a
model.

MOPAC in Chem3D
 MOPAC is a molecular computation application developed by
Dr. James Stewart and supported by Fujitsu Corporation that
features a number of widely-used, semi-empirical methods. It
is available in two versions, Standard and Professional.
 MOPAC Std. is available as an optional addin for Chem3D
Pro. MOPAC Pro is a standard feature of Chem3D Ultra.
 Chem3D MOPAC provides a graphical user interface (GUI)
that allows you to perform MOPAC computations directly on
the model in the Chem3D model window. As a computation
progresses, the model changes appearance to reflect the
computed result. Computations are limited in CS MOPAC to
250 heavy atoms.

GAMESS in Chem3D
 The General Atomic and Molecular Electronic Structure
System (GAMESS) is a general ab initio quantum chemistry
package maintained by the Gordon research group at Iowa
State University. It computes wavefunctions using RHF,
ROHF, UHF, GVB, and MCSCF. CI and MP2 energy
corrections are available for some of these.
 GAMESS is a command-line application, which requires a
user to type text-based commands and data. Chem3D serves as
a front-end graphical user interface (GUI), allowing you create
and run GAMESS jobs from within Chem3D.

Descriptors of SAR
 Chem3D provides a set of physical and chemical property
predictors. These predictors, which help predict the
structure-activity relationship (SAR) of molecules, are
referred to as SAR descriptors. The Chem3D Property
Broker provides an interface in Chem3D and
ChemSAR/Excel that allows you to calculate properties
using many calculation methods provided by various
Property Server components.

Property broker server in Chem3D
The components of the Property Broker-Server
architecture are illustrated below:

ChemProp Std Server
Connolly Solvent Accessible Surface Area
Connolly Molecular Surface Area
Connolly Solvent-Excluded Volume
Exact Mass
Molecular Formula
Molecular Weight
Ovality
Formal Charge

ChemProp Pro Server
Boiling Point
Critical Temperature
Critical Pressure
Critical Volume
Melting Point
LogP
Molar Refractivity

limitations
 Property prediction using CS ChemProp Pro has
following limitations:
Single molecules with no more than 100 atoms.
Literature values for Partition Coefficients (LogP) and
Henry's Law Constant are not available for all molecules.
Some atom arrangements are not parameterized for the
fragmentation methods used to calculate the properties.

MM2 Server
Bending Energy.
Charge-Charge Energy
Dipole Moment
Non-1,4 van der Waals Energy
Torsion Energy
Total Energy
van der Waals Energy

MOPAC Server
 Alpha Coefficients
 Beta Coefficients
 Gamma Coefficients
 Dipole
 Electronic Energy
 HOMO Energy
 LUMO Energy
 Repulsion Energy
 Symmetry
 Total Energy

GAMESS Server
Dipole Moment
HOMO Energy
LUMO Energy
Repulsion Energy Energy.
Total Energy

SAR Descriptor Computations
 Chem3D performs property prediction calculations.
 These computed properties are the descriptors that may
be used to estimate the structure-activity
Relationship(SAR) of molecules.

Selection of properties
 To select properties for computation:
1. From the Analyze menu, choose Compute Properties.
The Compute Properties dialog box appears.
2. Set appropriate values for the Class, Server, Cost, and
Quality filters.
3. From the list of Available Properties, select the properties
to calculate.
4. Click Add.

Property Filters
• Class-limits the list of available properties to types
calculations that you specify.
• Server-limits the list of available properties to those
properties computed by the servers you specify.
• Cost-represents the maximum acceptable computational cost.
It limits the list of available properties to those which are less
than or equal to the computational cost specified.
• Quality-represents the minimum acceptable data quality. It
limits the list of available properties to those with quality
greater than or equal to the quality specified.

Setting Parameters
 If a property has one or more parameters that affect the result
of the calculation, you can specify the values or calculation
method of those parameters. If several properties have the
same parameters, you can change the parameters
simultaneously.
To change a parameter:
1. Select the property or properties in the Selected Properties list.
2. Click Parameters.
3. Edit the value or select the method.
4. Click OK.

ALCHEMY 2000
 It is a graphic interface for running molecular
mechanics and semi-empirical calculations.
 Calculations can be done with the built-in tripos
force field or by calling the MM3 or MOPAC
programs, which are included with the package.
 Alchemy is designed by Tripos and sold by SciVision.
 Molecules can be drawn in 2D or 3D and can also be
inter-converted.
 Libraries of organic functional groups is available
and it also has protein builder.

ALCHEMY 2000
 The user can change stereochemistry or
conformational angle until he wants it to stop.
 Conformational searches using Tripos force field is
done up to eight single bonds and two rings.
 Output data can be exported to a spreadsheet.
 Structures can be labeled and rendered in several
different ways and can also be saved in different
formats or as an image. The presentation mode
allows molecular structure to be combined with text.
 The program allows to create a database and run
calculations on whole database.

REFERENCE
 www.google.com
 Manuals of different softwares
 www.sciencedirect.com
 Computational chemistry by David Young

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