Pharmacophore mapping and virtual screening

PHARMACOPHORE
MAPPING AND
VIRTUAL SCREENING
By;- Sanchit Dhankhar
Pharmacology Department

• CONCEPT OF PHARMACOPHORE
• PHARMACOPHORE MAPPING
• IDENTIFICATION OF PHARMACOPHORE FEATURE
• CONFORMATIONAL SEARCH
• INSILICO DRUG DESIGN
• VIRTUAL SCREENING
• PHARMACOPHORE BASED SCREENING
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 First introduced by Paul Heritich in 1990
 A pharmacophore is an abstract description of molecular features which are
necessary for molecular recognition of a ligand by a biological
macromolecule.
 It is the key features responsible for an activity (eg. Substrates, inhibitors)
 A pharmacophore is a representation of generalized molecular features
including;
 3D (hydrophobic group, chaeged /ionisable group, hydrogen bond donar/
acceptor)
 2D (substructure)
 1D (physical & biological)
H Aromatic HBA R HBD
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Pharmacophore Mapping is the definition and placement of
pharmacophoric features and the alignment techniques used
to overlay 3D.
Two somewhat distinct usages:
 That substructure of a molecule that is responsible for its
pharmacological activity (c.f. chromophore)
 A set of geometrical constraints between specificfunctional
groups that enable the molecule to have biological activity
The process of deriving pharmacophore is known as
pharmacophore mapping.
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1. Identifying common binding element that are
responsible for the biological activity;
2. Generating potential conformations that active
compound may adopt; and
3. Determining the 3D relationship between
pharmacophore element in each conformation
generated.
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 X-ray Crystallography
 Structure Comparison of active compound
 Automatic identification of pharmacophore
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4)PHARMACOPHORE MAPPING
SOFTWARE
 Discovery studio :
• Window ® and Linux® based protein modeling software. Produced by
Accelrys software company, easy to use interface.
 Examples of the programs that perform pharmacophore based searches are
• 3D search UNITY,
• MACCS-3D and
• ROCS.
 ROCS is using as shape based super position for identifying compound that
have similar shaped.
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5) CONFORMATIONAL SEARCH
X-ray Crystallography
Comparison of rigid & non rigid ligands
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 In Silico is an expression used to mean “performed
on computer or via computer simulation.”
 In Silico drug designing is defined as the
identification of the drug target molecule by
employing bioinformatics tools .
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LIGAND BASED
DRUG
DESIGNING
STRUCTURE
BASED DRUG
DESIGNING
IN SILICO
DRUG
DESIGNING
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1.Structure-based
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(know receptor, don’t known ligands)
• Relies on knowledge of the three dimensional structure of the
biological target obtained through methods such as
 x-ray crystallography
 NMR spectroscopy.
 homology modeling
• Using the structure of the biological target, drugs that are predicted to bind with to the
target may be designed using
 interactive graphics
 the intuition of a medicinal chemist.
 automated computational procedures

2.Ligand-based
(don’t know receptor, known ligands Protein/ligand)
• Relies on knowledge of other molecules that bind to the biological target of
interest.
• Used to derive a pharmacophore
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 Computational technique.
 Producing large libraries of compound that docked in
to the binding site using computer programme.
 The goal is finding interesting new scaffolds rather
than many hits.
 Low hits rate are clearly very preferable.
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 Usually pharmacophore based search are done in two steps.
• First the software checks whether the compound has the atom
types or functional groups required by the pharmacophore,
• than its checks whether the spatial arrangement of this
element matches the query.
 Flexible 3D searches identified a higher number of hits than
rigid searches do. However flexible searches are more time
consuming than rigid ones.
 There are two main approaches for including conformational
flexibility in to the search one is top generate a user defined
number of representative conformation for each molecules
when the database is to created, the other is to generate
conformation during the search.
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 Pharmacophore model provide powerful filter
tools for virtual screening even in case where
the protein structure is not available,
pharmacophore filter are much faster than
docking approaches, and there for greatly
reduce the number of compound subjected to
the more expensive docking application.
 Another interesting aspect of pharmacophore
in virtual screening is 3D- pharmacophore
diversity
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 Patrik G. L., an introduction to medicinal chemistry, 3rd
edition, page no. 340-345
 www.en.wikipedia.org
 https://www.slideshare.net>GamitKinjal/pharmacophore-
mapping-05
 https://www.slideshare.net/mobile/chinexcee/pharmacophore-
mapping-in-drug- development
 http://m.authorstream.com/presentation/aSGuest126841-
1335009-pharmacophore-mapping/
 https://www.slideshare.net/mobile/Deveshshukla 10/in-silico-
drug-designing
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