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Chapter

Global Ligand-Protein Docking

Tools: Comparation and Case Study
Vy T.T. Le, Tu H.T. Nguyen and Phuc-Chau Do

Abstract

Molecular docking study, a method used in drug discovery, is used to estimate the
interactions between small molecules and macromolecules. Docking can be divided
into rigid and flexible docking where local and global docking is the subclass in
the flexible approach. Two important criteria in docking are search algorithms and
scoring functions. The former assesses the fitness of ligand poses within the protein’s
binding site, while the latter explores different ligands “conformations until the point
at which the least energy convergence is achieved.” Three user-friendly global docking
programs (AutoDock Vina, MOE, and DOCK6) are utilized to study ligand behaviors
against Enterovirus A71 3C protease (3Cpro), which causes hand-foot-mouth disease
in children. The results suggested that the DOCK6 gives the fastest output, and all of
the ligands correctly bind to the active site of 3Cpro. Rupintrivir is a good candidate for
serving as a positive control in all three tools for binding site identification because
it shows broad resistance to viruses. In comparison to AutoDock Vina and MOE,
DOCK6 exhibits superior conformational space search efficiency and speed across
the three docking technologies used in our investigation. AutoDock Vina, however, is
typically regarded as being more appropriate for novices.

Keywords: scoring functions, search algorithms, rigid and flexible docking, global
docking, AutoDock Vina, MOE, DOCK6, Enterovirus A71, 3C protease

1. Introduction

In the fields of molecular biology and pharmacology, studying how ligands

interact with proteins is crucial because it plays a key role in comprehending basic
biological processes and developing therapeutic treatments. Ligands can be tiny
molecules, medications, or signaling molecules. Its function is to interact with
proteins to influence a variety of biological processes (e.g., enzymatic activity, signal
transmission, and gene expression). Scientists can gain crucial understanding of
the fundamental processes of disease etiology and possible paths toward treatment
by clarifying the molecular processes that underlie these interactions. Knowing
how ligands interact with proteins makes it easier to predict drug toxicity, efficacy,
and side effects, as well as to identify adverse reactions. This knowledge aids in
optimizing drug candidates for better pharmacokinetic and bioavailability during
drug discovery and development. Precision medicine techniques are made possible

1
Unravelling Molecular Docking – From Theory to Practice

by the rational creation of innovative treatments that are specifically targeted at

molecular targets or certain disease pathways, which is made possible by a thorough
understanding of ligand-protein interactions. The investigation of ligand-protein
interactions is fundamental to the advancement of pharmaceutical research, propel-
ling breakthroughs in drug discovery and development, and to our comprehension of
biology and disease.
Biological systems are incredibly flexible and adaptive; they can respond to
a variety of stimuli and maintain equilibrium. The intricate nature of signaling
pathways and transcriptional networks is demonstrated by the dynamic regulation
of gene expression. Their intricacy is highlighted by the way that many elements
interact, such as through protein-protein interactions and metabolic pathways.
Understanding emergent behaviors is hampered by breaking down distinct com-
ponents. Understanding the dynamic nature of biological systems requires the
application of integrated viewpoints. Due to their transient and reversible character,
as well as their dynamic conformational changes, protein-ligand interactions present
difficulties in these kinds of systems. Interactions are further complicated by vary-
ing cellular architecture and subcellular localization patterns. Temperature, pH, and
posttranslational changes are among the factors that make it difficult to measure
interaction specificity precisely.
Drug development problems require multidisciplinary approaches that combine
computational modeling and experimental methods, such as structural biology.
In order to assist identify leads against macromolecules, virtual screening and
molecular docking have become effective methods for high-throughput screening.
Molecular docking is famous for identifying novel lead compounds rapidly against
macromolecules since 1980s due to the significant growth in computing power and
abundant availability of molecular structures [1]. These methods provide insights
into molecular mechanisms and binding affinities by modeling interactions between
proteins and ligands. To aid in the search for new drugs, docking studies forecast
ligand selectivity and off-target effects. Understanding protein-ligand interactions
in biological systems is improved by combining experimental techniques with dock-
ing simulations [1].
To perform docking, two approaches can be applied, namely, rigid and flexible
docking. A report carried out by Xuan-Yu Meng and his colleagues defined a rigid
docking where ligands and proteins maintain fixed conformations during docking
process, neglecting the flexibility and dynamic movements of the molecules. Then,
Fischer proposed a new approach, which is to measure the geometric fit between
their shapes is directly comparable to their affinity, and is known as the lock-and-
key theory [2]. Specifically, in the simplest rigid-body systems, to fit the protein’s
binding site, ligands undergo the search in a six-dimensional space including
rotational and translational changes via multiple interactions (e.g., van der Waals
forces, coulombic interactions, and hydrogen bonds). As a result, docking poses are
generated as the output, which will be ranked according to their scores, and the most
favorable ones will be selected, which might imply the active site of that protein.
However, the rigid body docking does not satisfy the experimental reality that
molecules, especially proteins, are crystallized separately. The three-dimensional
structure of protein primarily determined its function. This is defined by intricate
macromolecules composed of linear chains of amino acids, is highly dynamic, and
constantly changes conformations, which can significantly affect the overall shape
complementary and interactions with ligands [3]. Moreover, assessment of accuracy
in docking is preferable in bound complexed rather than unbound ones, indicating
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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

that treating proteins as entire rigid body is not certified [1]. The induced fit
approach was first introduced by Koshland et al. in 1963. It suggested that proteins
and ligands be flexible during docking to accommodate the dynamic nature of the
system [4]. Partial or fully flexible methods, where local changes or entire protein
conformations are allowed to vary, are included in flexible docking. While fully
flexible docking incorporates side chain and backbone changes, partial flexibility
concentrates on particular regions of the molecular structure. Through the investiga-
tion of various conformational changes, these techniques bolster the binding mode’s
accuracy as well as predict binding affinity efficiently. Large conformational spaces
can be efficiently explored with the help of technological advancements, such as
graphics processing units (GPUs), which increase computing efficiency for extensive
searches [1].

2. Global docking for protein-ligand system

Global docking or blind docking refers to a method where a ligand (small mol-
ecules) will be docked to a whole surface of a target receptor (typically a protein)
without knowing prior to the receptor’s binding site. To be more specific, the process
searches for the entire conformational space of both ligand and receptor to determine
the most favorable interaction and binding poses (Figure 1). While local docking
focuses on flexibility at the specific site of docking, global docking allows all the rigid,
flexibility, and orientation of both molecules, which might require more resource
requirements and running time.
Good global docking results require careful consideration of numerous crucial
parameters. The precision of the protein structure employed for docking is critical.
Docking accuracy improves when both the protein and the ligand are properly pre-
pared, including the removal of water molecules and the adjustment of protonation
states. Furthermore, it is critical to select appropriate scoring systems that accurately
measure binding affinity and to incorporate flexibility in both the protein and the
ligand during simulation. Docking results can be validated against experimental
data to ensure trustworthiness, while efficient sampling techniques and taking into
account solvent effects enhance prediction accuracy. Recently, there have been more

Figure 1.
Local docking and global docking of an aminoglycoside antibiotic, gentamicin (green), and the 16SrRNA a site of
bacterial ribosome. Pink and yellow residues are the binding sites estimated by RLDOCK [5].

3
Unravelling Molecular Docking – From Theory to Practice

than 60 docking programs and servers appearing to be available for academic or com-
mercial purposes [6–8]. The differences among these docking tools are a scoring func-
tion and a search algorithm in estimating the binding modes and affinities between
proteins and ligands (Table 1). The capability of sufficiently sampling the degrees of

No Tools Year Scoring functions Search algorithms Lisence

1 ICM [9] 1994 Internal Coordinate Mechanics Monte Carlo, Academic free
scoring Recursive Belief-based
Learning

2 Flex X [10] 1996 Ludi score, Chem score, FlexX Incremental Commercial
score Construction, Branch
and Bound

3 Gold [11] 1997 Gold Score, Chem Score, Genetic Algorithm, Commercial
Astex Statistical Potential, Monte Carlo
ChemPiecewise Linear Potential

4 DOCK6 2003 Contact score, Grid-based Anchor-and-grow, Academic free

[12–16] score, DOCK 3.5 score, De novo, Genetic
Continuous score, Zou Algorithm,
Generalized-Born/ surface area, sphere-matching
Hawkins Generalized-Born/
surface area, AMBER score,
Footprint score, Multigrid
score, Pharmacophore
Matching Similarity, Internal
Energy Simple Score, Solvent
Accessible Surface Area score,
Descriptor score

5 Fred (Fast 2003 Screenscore, Chemgauss, Shape-based Commercial

Rigid Shapegauss, ChemScore and (Gaussian)
Exhaustive Piecewise Linear Potential
Docking) [17]

6 Surflex [18] 2003 Surflex score Broyden-Fletcher- Commercial

Goldfarb-Shanno

7 Gemdock 2004 Simple empirical scoring Evolutionary Free

[19] function and a pharmacophore- algorithm
based scoring function

8 AutoDock 2010 Standard Vina scoring Monte Carlo-Broyden- Academic free

Vina [20, 21] Fletcher-Goldfarb-
Shanno

9 Symmref [22] 2011 Energy scoring function Symmref algorithm, Free

Monte Carlo-
Broyden-Fletcher-
Goldfarb-Shanno

10 MOE [23] 2012 Systematic and Stochastic Atom-sphere Academic free

sampling exclusion score,
Affinity ΔG score,
Alpha Hydrogen Bond
score, London ΔG
score and Generalized
Born-Volume Integral/
Weighted Surface
Area ΔG score

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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

No Tools Year Scoring functions Search algorithms Lisence

11 LeDock [24] 2013 Chemscore, Piecewise Linear Simulated annealing Free

Potential and genetic algorithm

12 PyRx [25] 2015 Random Forest-based scoring Monte Carlo-Based Free

function for Virtual Screening Search, Lamarckian
Genetic Algorithm,
Iterated Local Search,
Local Optimization

Table 1.
Selected global docking tools.

freedom (rotation and translation) within the complex system to ensure the actual
binding modes are counted has proven to be an effective characteristic of basic search
algorithms. Meanwhile, scoring function’s role is to predict the binding free energies
( D G bind) within a specific range, followed by the evaluation of the true binding
modes and finally ranking poses based on predicted binding affinities.

2.1 Searching algorithm

Effective methods are essential for precise global docking, wherein the root mean
square deviation (RMSD) is employed to measure ligand position in relation to
experimental data. Due to computational limitations (considering just six degrees of
freedom: rotation, translation, and conformational change), rigid body approxima-
tion was initially popular. However, it has constraints in describing particular inter-
actions between ligands and binding sites. Certain programs maximize computing
resources, improve interaction realism, and provide complete ligand variation while
restricting the flexibility of proteins. Conformational alterations in ligands or recep-
tors are referred to as flexibility in docking. The three types of flexible ligand docking
methodologies are simulation, stochastic, and systematic searches.
The aim of the systematic search methods is to systematically cover the entire
search area of possible ligand’s configurations. They are subsequently divided
into three subcategories, namely, exhaustive, fragmentation, and conformational
ensemble methods. The first method, exhaustive search, involves the rotation at 360°
of all possible rotatable bonds in ligand at predefined intervals, but some challenges
arise with combinatorial explosion, restricting its practicality in exclusively small
and flexible ligands [6]. Meanwhile, fragmentation approach splits the ligands into
modular parts, and one of its fragments is placed immovably in the receptor’s bind-
ing site, followed by adding other flexible parts to complete the ligand structure.
Regarding conformational ensemble approach, despite minimizing the computational
costs because pre-formed ligand conformations are used, generating such conforma-
tional ensembles requires additional tools and bioactive structures may sometimes be
neglected.
In the context of stochastic algorithms, random alterations based on predefined
probability functions are either accepted or rejected to seek ligand binding orienta-
tions and conformations. Hence, a global energy minimum has risen due to a variety
of conformational space of ligands, as well as energy landscapes discovered. However,
as a large search space is examined, this results in computational extensive. There
are four basic categories: Genetic Algorithm (GA), Monte Carlo (MC), Ant Colony
Optimization (ACO), and Tabu Search (TS). The first group-MC method was
5
Unravelling Molecular Docking – From Theory to Practice

primarily applied in the minimization step in molecular dynamic (MD) simulations

(e.g., GROMACS [9]). Its principle lies in applying the Boltzmann probability func-
tion to calculate the chance of accepting random fluctuations in thermodynamically
accessible states, which decreases the chances of being trapped in local minima [10].
Secondly, GAs are derived from evolutionary programming algorithms (employ
evolution-driven computational models) designed to determine the precise conforma-
tion to the global energy minimum. Meanwhile, TS method is an iterative optimization
process and a variation of GA method [1]. It functions as a meta-heuristic method that
can switch from one solution to another while keeping previously visited solutions
in memory. However, TS separates itself from local search strategies by integrating a
memory structure (Tabu list) to prevent the return of already guessed solutions and to
encourage further exploration of new regions [11]. The principle of the last ACO type
aims to apply pheromone trails for marking the low-energy ligand structures, which
are altered in further repetitions to produce apparently low-energy conformations [12].
While systematic search focuses on thoroughly exploring the whole conforma-
tional space in a methodical manner and the objective of stochastic search is to select
the optimal ligand conformations based on a predetermined probability function,
simulation search involves solving Newton’s equations of motion. MD and pure
energy minimization methods stand out as the two main types of this approach. The
former considers forces and motions in the molecular behaviors over the time, but it is
limited in locating rugged hypersurfaces and productively sampling different ligand
structures within an appropriate simulation period. Meanwhile, the latter requires
the most robust system possibly by reducing the potential energy of the system. It
comprises diverse techniques such as direct searches, gradient methods, or conjugate-
gradient methods (e.g., Fletcher-Reeves) and is often used complementarily with
other docking algorithms [13–15].
Several docked structures with favorable surface complementarity are built on the
topic of rigid body approximation and then reorganized in relation to free energy. The
fast Fourier transform (FFT) correlation method explores systems docked structures
via electrostatic interactions or a combination of electrostatic and solvation terms
[6]. Other features, such as atomic interaction properties, relative shape, dissociation
energies, polar Fourier interactions, and advanced software/hardware technologies
to accelerate outputs, are incorporated in some FFT-based methods [16, 17]. Another
algorithm utilized in rigid body docking, which aims to determine complementarily
molecular shapes using such surface patches or 3D Zernike descriptors and thus
aid better alignment of local geometric feature, is known as the geometric hashing
(GH) method [18]. Likewise, shape matching (SM) algorithms evaluate geometric
overlap in identifying optimal matching between ligands and receptor’s binding site
[19]. DOCK tool – a pioneer in employing both SM and GH algorithms to recognize
potential binding sites – sphere centers [20].

2.2 Scoring function

With the advance in computational hardware, the primary challenges have shifted
from search-related algorithms to those involving scoring. Specifically, the challenges
in D G bind’s prediction should be considered, such as complex physical interactions –
entropy and enthalpy (e.g., interacting bonds, solvent molecules, entropy loss due
to rotation and translation of ligands). This leads to the idea of being simplified and
assumptive in scoring functions to decrease the complexity of the systems, as well
as balancing the speed and accuracy are crucial to avoid errors. Ideally, an optimal
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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

search algorithm comes along with the best scoring function, which is contrary to
current docking tools depending on the specific characteristics of receptor’s bind-
ing sites and studied ligands, so making the method become impractical [10]. In the
realm of scoring functions, it is categorized into three basic groups, namely, physics-
based, empirical, and knowledge-based functions to forecast how strong the interac-
tions between proteins and ligands are (Table 2). Each class contributes to advancing

Aspects Physical-based Empirical Knowledge-based

Principle Enthalpy contribution The addition of different The distance-dependent

is considered along with energetic terms ranging pairwise potentials are
the sum of bonded and from hydrogen bonds to transformed from the atom
non-bonded interactions hydrophobic effects is pairs using the Boltzmann law
within the complex. then multiplied with a after obtaining the occurrence
coefficient derived from frequencies of the protein-
linear regression analysis. ligand complexes’ structural
information in a database

Advantages Evaluation the binding Simple energy term Affordable for large scale
poses quickly, suitable treatment makes faster database
for high-throughput computation Robust to training set diversity
docking. Preferable for virtual Effective differing the binding
Alignment with modern screening modes.
force fields Extension to many-body
Obtaining from interactions
fundamental physics More variable in ligand
principles flexibility
Computational
cost-effective

Challenges Restriction in Not consider the Reference state determination

approximations involvement of solvents Issues relating to potential
Ignoring the long-range explicitly energy accuracy.
binding effects, solvent Multiple energy terms are Less sensitive to solvent effects
effects and entropic double-counting issue. Entropic energy makes difficulty
terms makes inaccurate Limited description of in accurate calculation.
for complex and real flexibility Sensitive to ligand positions
biological systems. Reliant on training set
Rigid body assumptions quality causes lack of
are challenges in ligand generality
and protein variations

Recent Refinements Introduction of Iterative methods for

advances in electrostatic continuous, non-linear improving accuracy in ITScore,
interactions, ligand terms and ligand poses’ including solvation effects and
desolvation energies. variation in functions configurational entropy.
Post-scoring docking leads to the Hammerhead Quantitative structure-activity
applying the treatment and Surflex functions. relationships (QSAR)-Machine-
of solvent molecules as Machine-learning learning (ML) approach based
continuum dielectric approaches in some on distance-dependent atom pair
medium to accelerate empirical scoring occurrences.
force field models. functions

Examples Goldscore, AutoDock, Chemscore, Glidescore, Drugscore, RF-score, ITscore.

Generalized Born/ ChemPLP
surface area model

Table 2.
Comparison among three basic scoring function [1, 10, 21–23].

7
Unravelling Molecular Docking – From Theory to Practice

our understanding of molecular docking and holds implications for various applica-
tions from lead optimization to virtual screening in drug discovery.
In addition to the basic scoring functions mentioned above, many improved scor-
ing approaches have been evaluated, but they are limited to a specific task [1]. Thus,
scientists have raised up the idea of combining multiple scoring functions to tackle the
errors from individual function, which is termed the consensus scoring method. In
order words, best-docked pose of each compound will be reassessed using diverse scor-
ing functions and the compounds that frequently ranked top scored across all func-
tions are determined as potential candidates for further assays [10]. Take X-SCORE as
an example of consensus scoring technique that combines various scoring functions
or algorithms such as ChemScore, FlexX, DOCK-like, and GOLD-like [24]. Despite
being concerned about error amplification, consensus scoring function still proves its
capability in ranking effectiveness or false positives reduction. Another approach that
is developed these recent years is to apply ML – the random forests, and the convolu-
tional neutral network – in scoring function, principally introducing QSAR analysis to
assess the interaction between proteins and ligands [1]. This method involves multiple
properties of the complex such as atom pairs, geometric factors, and ligand-based
characteristics to build models for evaluating the binding scores. The process involves
two stages. Initially, ML automatically learns the known structure and binding infor-
mation from a training dataset, which is similar to empirical scoring approach. Then,
ML will be trained and builds its own mathematical formulas to rank and screen with
better accuracy than other basic scoring approaches. Some relevant ML scoring func-
tions are random forest-based score, and support vector machine score [25].
Above algorithms are generally applied for flexible ligand docking, which could be
employed for flexible receptor docking, but obtaining the results at a reasonable time-
frame is not yet addressed due to an increased in dimensionality and hence computa-
tionally intensive for a larger search space. One solution is to use intricated algorithms
combined with simulations to effectively locate the expanded search space, but this
still accounts for too much computational resources. Other well-known approaches,
including rotamer libraries, soft-receptor modeling, and ensembles of protein confor-
mations have been developed with the purpose of simplifying the system’s approxi-
mation, accompanied by a reduction in computational costs. The transition to using
different global docking tools on a given system necessitates a thorough examination
of each tool’s performance characteristics. This evaluation ought to consider a variety
of factors such as the accuracy of anticipated binding poses and binding affinities,
the productivity of computing resources employed, and the algorithm’s resistance to
fluctuations in input parameters. Furthermore, assessing each tool’s virtues and draw-
backs reveals important information about its underlying algorithms and approaches.
Such extensive comparison studies allow researchers to make educated judgments
about which docking tool is most suited to their individual research needs, enhancing
the accuracy and usefulness of docking results to research objectives.
In this book chapter, we carried out a case study on the 3C protease (3Cpro) of
Enterovirus (EV) – A71 that causes hand-foot-mouth disease (HFMD) in mostly
children worldwide. A series of ligands, which have been assessed for their antiviral
properties against different mutated EV-A71 3Cpro, were tested using three common
docking tools AutoDock Vina [26, 27], MOE [28], and DOCK6 [20]. Subsequently,
their docking poses were assessed to identify the active site based on their proxim-
ity to the binding site. Ultimately, a comparative analysis on different criteria (e.g.,
execution time, setting, process on multiple ligands) was also carried out for further
conclusion.
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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

3. Case study in 3Cprotein of Enterovirus A71

HFMD, which is primarily caused by EV and Coxsackievirus (CV), belonging to

Picornaviridae family, is a pediatric disease mostly targeting children under the age
of five [29]. Reports found out that EV-A71 displays more severe consequences such
as dysfunction in the central nervous system, cardiopulmonary failure, or vesicular
eruptions on feet, hands, and oral mucosa than CV-A16 or other strains [30]. EV-A71
was initially discovered in 1957 in New Zealand and then isolated from an encepha-
litis female’s face in 1969 in California [30, 31]. Then, in the late twentieth century,
many outbreaks of HFMD had been detected in all over the world, and most large
expansions of this serious disease occurred in Asia-Pacific areas, which resulted
in unattainable severity tracking. Unfortunately, there are limitations in available
vaccines against these strains of EV-A71 and only symptomatic-supportive treatments
are available [36]. Thus, these have raised an emergency alarm for thorough studies
on different strains with existing inhibitors as well as leveraging for new potential
candidates against EV-A71.
EV-A71, which attaches to host cells by different receptors, has a single-stranded
RNA genome. This facilitates the uncoating and viral replication processes [32].
There are four categorized regions in EV-A71 genome denoting from P1–P3 in which
P1 is responsible for VP1–VP4 while seven non-structural proteins belong to P2 and
P3 groups. During the maturation of EV-A71, 3C protease (3Cpro) – one of the P3’s
subclasses, which is a chymotrypsin-like fold structure, involves in cleaving the viral
polyprotein at eight distinct sites [33]. Another role of 3Cpro is the cleavage of essential
eukaryotic initiation factors, which results in preventing host cap-dependent transla-
tion [34]. A report carried out by Wang et al. revealed that the binding site of 3Cpro
contains three key amino acid residues (His40, Glu71, and Cys147) which is responsible
for cooperatively promoting substrate cleavage [35]. Additional to the catalytic impor-
tant loop is the 3Cpro cleavage site involving such several main amino acid residues:
Tyr122, Phe124, Glu126, Leu125, Leu127, Ser128, Thr142, His161, Ile162, Gly164, and
Phe170 [36]. In our previous study, these two mentioned binding sites, which had been
discovered earlier by Wang and Lu’ groups, are preferable for most inhibitors [35, 37].
Thus, these binding sites could be considered as the active site of 3Cpro proteins.
Furthermore, viral mutations are unavoidable, resulting in the formation of new
viral variants with changed antigenic features, which may lead to immune evasion
and reduced efficiency of current vaccines and treatments, as well as research chemi-
cals. Furthermore, some mutations may give resistance to antiviral medications,
reducing their effectiveness in treating viral infections. Thus, understanding how
mutations affect the binding of ligands globally is crucial in order to cope with the
viral evolution and variations in 3Cpro sequences.
In our study case, three models of 3Cpro proteins are selected, including the wild-
type strain (PDB ID: 5C1U) and two mutant strains (PDB ID: 5GSW, 3QZQ ). Besides,
five prospective ligands are considered for docking. Rupintrivir, one of the synthetic
drugs used to treat HFMD, has proven to pass the first phase of clinical test success-
fully. Meanwhile, two additional synthetic compounds – an isopropyl-substituted
4-iminooxazolidin-2-one moiety (FIOMC) and an a -keto amide derivative (8x),
alongside with two naturally occurring compounds belonging to the flavonoid family
(rutin and luteoloside) – are chosen due to their potent inhibitory effects on the
3Cpro proteins [36]. The active site of 3Cpro proteins was identified in our prior work
and displayed in Figure 2 below. Hence, ligands residing at the peptide’s position are
recognized as the promising antiviral substances against 3Cpro proteins.
9
Unravelling Molecular Docking – From Theory to Practice

Figure 2.
Binding sites of 3Cpro protein (PDB ID: 5C1U) with a) six clusters generated when 5C1U docked by AutoDock
Vina with 21 control candidates, b) experimental 3SJ9, and c) 3SJK between 3Cpro (gray color) with its targeted
peptide (yellow color) [36].

3.1 AutoDock Vina

AutoDock Vina is widely used due to its user-friendly interface for molecular
docking and virtual screening. In 2009, Dr. Oleg Trott and his team at molecular
graphics lab at the Scripps Research Institute, USA, developed this tool from
AutoDock 4.0 (AD4.0) [38]. Then, AutoDock Vina 1.2.0 was reported by Jerome
et al. with additional support in the treatment of water molecule explicitly and
multiple ligands docking (cite). Currently, a newest version of AutoDock Vina
1.2.5 is available at center for computational structural biology website (https://
vina.scripps.edu/), belonging to Dr. Oleg’s lab. Alongside with other docking
engines in AutoDock Suite package [38–40], AutoDock Vina recognizably outper-
forms with AD4.0 for being 100 times faster, as well as significantly reduce the
running times via exploiting multiple CPUs or CPU cores. Moreover, its accuracy
in binding mode predictions is also upgraded by employing efficient search algo-
rithms and assessing fewer scoring functions. In addition, some parameters, that
have proven to be well-performed in diverse scenarios, are automatically set. This
allows the software to be more accessible and straightforward for either experts or
nonexperts in the field.
AutoDock Vina’s configuration file has adjustable options that accommodate
different system sizes and docking goals. Coordinates and box size are adjusted in
global docking scenarios to sufficiently encompass the target region. Docking perfor-
mance can be adjusted with flexibility using parameters, such as exhaustiveness value
(default = 8) and energy range (default = 4 kcal/mol). While more exhaustiveness
improves conformational exploration, it also increases computing times. Energy
range modification impacts docking diversity and fidelity, as well as posture selection
strictness. Rupintrivir’s broad antiviral spectrum is shown by the AutoDock Vina
results, which show preferential ligand binding to active sites (Figure 3).
As mentioned above, scoring functions and search algorithms are the major fea-
tures in assessing the performance of a docking software. In the latest AutoDock Vina’s
version, it includes both AD4.2 and Vina scoring functions. This is because Vina lacks
some parameters that are present in a physics-based model – AD4.0 such as directional
hydrogen bond potentials, electrostatic, and solvation [26]. Additionally, deriving from
both knowledge-based and empirical scoring functions, the ligand conformational space
and its interactions with receptors are assessed thoroughly. This effectively heightens the
10
Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

Figure 3.
Binding poses formed by AutoDock Vina between control ligands (line presentation) on three 3Cpro models
(ribbon presentation).

system’s accuracy. Pertaining to search algorithms, even though various stochastic global
optimization approaches have been exploited in the evolution of Vina. Thus, a similar
method developed by Abagyan et al. is known as Iterated Local Search global optimizer
[27]. Thanks to the ability in using multicore CPUs in Vina, this intensive iteration can be
done efficiently in an acceptable timeframe.
However, this is contradicted to what we researched earlier using the exhaustiveness
value of 256 that FIOMC displays the best antiviral characteristic across the broad range
of virus strains. Besides, the number of binding sites in the wild-type strain is more
11
Unravelling Molecular Docking – From Theory to Practice

condensed than in the others. With regard to two mutant proteins, 5GSW is mutated
from an asparagine to serine at position 69, while the glutamic acid is mutated to aspartic
acid at position 71 in 3QZQ. It is noticeable that the ligands tend to be more dispersed
than in the case of 5GSW, which agrees to our previous study [36]. Regarding the average
time for one 3Cpro model with five ligands, it is estimated about 2 hours for a triplicate
run with a default exhaustiveness value. This is because AutoDock Vina allows for
maximum of 20 modes per single docking performance, so each pair of protein ligand is
docked three times with different random seed numbers in order to produce more bind-
ing poses for a better evaluation, as well as reproducibility.

3.2 DOCK6

DOCK was initially built by Sheridan et al., implementing geometric matching

and distance-based comparisons to find the most favorable binding poses in 1986
[41]. Since then, it has been remarkably evolving with additional essential features,
such as Hawkins-Cramer-Truhlar Generalized Born/Surface Area (GB/SA) solvation
scoring and Poisson–Boltzmann/Surface Area (PB/SA) solvation scoring through
OpenEye’s Zap Library. This leads to the release of the newest version of DOCK6
developed by Therese Lang et al. and his collaborators in 2009 [20, 42–45]. This new
version has more functions, such as receptor flexibility consideration and conjugate-
gradient minimization via accessing the NAB library. In addition, more scoring
functions are also introduced in DOCK6 as described in the web manual. Regarding
sampling methods, DOCK6 implements several advanced algorithms to study specific
interactions between ligands and proteins (e.g., anchor-and-grow, de novo, GA, and
Hungarian algorithm) [46].
For the purpose of selecting spheres and generating DMS (Database Management
System) files to store structure management, DOCK6 needs UCSF Chimera. Docking
box construction is dependent on selected spheres, as seen by the UCSF Chimera
sphere table. When global docking conditions are met, the protein is covered entirely
by the “0” option. For steric overlaps and fast score evaluation, grid creation uses
bump and scoring grids, which are modifiable based on the task at hand. Every
scoring algorithm operates independently, with results stored in separate files. Ligand
energy minimization – which can be adjusted using DOCK6 scripts – is essential to
lessen atomic collisions. For best results, flexible ligand docking requires modifying
parameters, such as number_scored_conformers and rank_ligands [46]. Long dock-
ing periods and resource demands result from the search algorithm’s limited ability to
manually customize boxes while effectively identifying 3Cpro binding locations.
The docking tasks in DOCK6 are faster compared to Vina, even when utilizing
default settings. The process takes approximately less than 30 minutes for a single
system, comprising one protein model and five ligands. Although DOCK6 is imple-
mented with multiple scoring functions, a default grid score is used in our study case.
Furthermore, DOCK6 utilizes an anchor number to determine the generated modes
of ligands, making a single run adequate for assessment. Looking at the docking
results in Figure 4, it is observable that all of ligands interact at the active site of
3Cpro protein within three studied models. As a result, DOCK6 is more efficient in
defining the active site of the targeted protein via evaluating the spheres covered the
favorable binding sites in comparison to AutoDock Vina. Furthermore, we notice that
rupintrivir binds more accurately at the active site than other ligands, which is similar
to the above AutoDock Vina’ results. Overall, there is not much different among these
models when using DOCK6 for docking.
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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

Figure 4.
Binding poses formed by DOCK6 between control ligands (line presentation) on three 3Cpro models (ribbon
presentation).

3.3 MOE

Paul Labute, the President and CEO of Chemical Computing Group, which was
established in 1994, is located in Montreal, Quebec, Canada (cite web). The team’s
goal is to generate innovative tools that not only confront the existing norms but also
transform scientific approaches. Thus, the launch of MOE demonstrates the com-
pany’s dedication to the generation of cutting-edge solutions that remarkably assist
in the development of computational chemistry research area. Its operation can carry
out in multiple systems (https://www.chemcomp.com/Products.htm).
In regard to the docking time, it is noticeable that MOE requires the longest
time ( ³ 1.5 hours) for a pair of protein ligand to produce 100 binding poses. When
13
Unravelling Molecular Docking – From Theory to Practice

assessing the percentage of poses at the active site, Rupintrivir ranks the best potent
compound in interacting with 3Cpro proteins at that site, while FIOMC and rutin bind
at the opposite site (Figure 5).
Moreover, ligands tend to scatter in all cases due to default search algorithm
setting. Apart from the wild-type strain, two other mutant strains show opposite
results compared to two previous tools. In particular, ligands distributed more neatly
in 3QZQ case, compared to 5GSW, where three out of five ligands do not bind at the
active site. This is contrast to our earlier study that mutation in 5GSW did not show
many impacts on the binding of ligand rather than that of 3QZQ [36].

Figure 5.
Binding poses formed by MOE between control ligands (line presentation) on three 3Cpro models (ribbon
presentation).

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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

The rational in choosing the parameter depends on the purpose of docking.

Among them, the pharmacophore only supports the commercial version. Meanwhile,
the other scoring functions can be changed depending on the interested interactions
(e.g., Atom-Sphere Exclusion, Affinity D G scoring, Alpha Hydrogen Bond scoring,
and GBVI/WSA), alongside with several crucial factors, including atom-atom interac-
tions, geometric fit, H-bonding, and energy contribution. In our study case, default
settings are employed for all systems that use triangle matcher in placement; London
D G in rescoring, and no refinement is set.

4. Conclusion

In conclusion, this study examined several scoring functions and search algo-
rithms in docking software, as well as the field of docking approaches, identifying
local and global docking. This discussion centered on global docking, more especially
on complete and partial flexible docking. In order to identify protein binding sites,
three popular docking tools – AutoDock Vina, MOE, and DOCK6 – were evalu-
ated using a case study containing the EV-A71 3C provirus that causes HFMD.
Interestingly, DOCK6 outperformed the others in displaying concentrated ligand
poses in the 5C1U protein’s active regions, while AutoDock Vina provided information
about how mutations affect ligand interactions.
In order to evaluate the quality of docking results and support the logical design
of new therapies, post-docking analysis requires accurate binding energy prediction.
However, this is not possible at this level of global docking because the main goal is to
evaluate receptor binding locations. These binding energy values must be ascertained
by additional analyses, such as MD simulation or calculations utilizing the molecular
mechanics (MM)/PBSA or MM/GBSA methods. Meanwhile, by utilizing the AMBER
score and a basic MM-GB/SA method, DOCK6 assesses binding energy.
Regarding the study case, rupintrivir (AG7088) consistently showed excellent
inhibitory activity across both wild-type and mutant 3Cpro animals, establishing it as
a reliable positive control despite the variation in the data. All ligands docked at the
active site of 3Cpro proteins in DOCK6 with the fastest time in less than 5 minutes for
each pair of protein ligand when 100 poses are generated. Meanwhile, MOE does not
appear to support a comprehensive evaluation of a putative binding site, depending
on the quantity of produced ligands posed at various binding sites. Furthermore, the
likelihood that ligands will bind to 3Cpro proteins is affected by mutations in either
5GSW or 3QZQ. As a result, the docking findings produced by MOE show something
different from what we saw in AutoDock Vina’s previous studies (Table 3).
Default settings are frequently used since developers propose them for the
purpose of tool comparison. However, as many possibilities have been covered
previously, it is crucial to choose settings that are appropriate for the research aims
in order to produce the best results. To guarantee a more complete understanding of
protein-ligand interactions in the quest for drug discovery and design, researchers
may investigate other technologies in the future to improve and build upon current
discoveries. Efficient molecular docking for big chemical libraries is made possible by
developments in computational resources, such as cloud and distributed computing.
Processing operations on GPUs are accelerated, particularly when large conforma-
tional landscapes are being explored. Advancements such as cryo-electron micros-
copy offer abundant three-dimensional information, augmenting understanding of
protein structure and maybe boosting docking accuracy. Pose prediction accuracy is
15
16

Unravelling Molecular Docking – From Theory to Practice

System requirement Advantages Disadvantages

AutoDock Vina • Support for 64-bit Linux, Mac OS X 10.15 (Catalina) or • Less settings: grid box, exhaustiveness value • Ligands and proteins in must
later versions, SGI IRIX, and Microsoft Windows PDBQT format, which is not
• Perform docking for multiple protein -ligand systems at
ready to use
• Hardware: ³ 4GB RAM once with a Perl script
• Higher exhaustiveness value
• Disk space: ³ 100 MB • An open–source software with widely used globally
requires extensive computational
promotes scientific cooperation and continual progress to
• Compatible with CPUs only resources.
address any difficulties
• Simple command–line interface: easy use • Complicated systems require
• Flexible ligand docking options
• MGLtools is perquisite for preparing ligand and receptor longer timescale.
• Academic free
docking inputs • Limited side chains of receptors
flexibility.
• Solvation models by hydrated
docking, prefer for AutoDock4
rather than Vina

DOCK6 • Support for Linux or Windows (Unix-like environment – • Fast docking process for a default setting • Limited in the manual custom-
Cygwin); Mac OS with GNU compilers and configuration ization of the box
• Efficient search algorithms
files
• Multiple parameter settings to
• Decrease sampling
• Hardware: ³ 4GB RAM evaluate
• Various scoring functions help reducing scoring failure
• Disk space: ³ 200 MB • Require intensive computational
• Solvation models and flexible receptors docking: tackled resources for AMBER score
• CPUs for basic dockings and GPU compiler
by AMBER score docking
• Command-line interface: easy to use
• Flexible ligand docking option • Need to use with other programs
• Available free
17

DOI: http://dx.doi.org/10.5772/intechopen.1005158
Global Ligand-Protein Docking Tools: Comparation and Case Study
System requirement Advantages Disadvantages

MOE • Support in Windows, Linux, MacOS • Allow multi-tasking with command line • Uncommon command language
SVL
• Hardware: ³ 4GB RAM • Can customize wall constraint for each protein
• More time is needed for a
• Disk space: ³ 1GB • Unlimited number of poses per experiment
complex system
• Potential energy computations: 8 CPUs requirement • Support many file formats
• More pharmacophore is required
• Command-line and graphical interface unit: easy to use • Flexibility of receptors with several limited side chains for ³ 10 movable bonds
• Flexibility of ligands with £ 10 rotatable bonds • Solvation models handling for
• Increases adaptability by several search strategies the commercial version solely

• Maintains original geometry to improve search efficiency • Require ring structures to be

and precision generated in advance
• Commercial tool

Table 3.
An analysis of the three docking systems’ respective system requirements, benefits, and drawbacks.
Unravelling Molecular Docking – From Theory to Practice

increased by methods, including interaction fingerprints, better MM/PBSA analysis,

and pharmacophore modeling integration. The development of drug delivery devices
is aided in comprehending complex dynamics and binding processes by combining
docking with MD simulations. Enhancing docking technologies, such as optimiz-
ing metaheuristics for accurate pose prediction, is possible with AI, especially with
deep learning and machine learning. By iteratively retraining using informative
data, active learning minimizes the need for screening resources while optimizing
prediction reliability. Support vector machines and random forests are examples of
machine-learning algorithms that outperform traditional score methods in terms of
accuracy, which helps in ligand ranking. Drug research and design are improved by
deep learning methods, such as convolutional and recurrent neural networks, which
extract spatial and sequential information from 3D structures. The combination of
AI and ML has the potential to transform docking tools, speed up the hunt for novel
therapies, and enable more efficient drug discovery and design than is possible with
current methods.

Conflict of interest

The authors declare no conflict of interest.

Other declarations

None.

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Global Ligand-Protein Docking Tools: Comparation and Case Study
DOI: http://dx.doi.org/10.5772/intechopen.1005158

Author details

Vy T.T. Le1,2, Tu H.T. Nguyen1,2 and Phuc-Chau Do1,2*

1 School of Biotechnology, International University, Hochiminh City, Vietnam

2 Vietnam National University, Ho Chi Minh City, Vietnam

*Address all correspondence to: [email protected]

© 2024 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
19
Unravelling Molecular Docking – From Theory to Practice

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