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1.  istar: A Web Platform for Large-Scale Protein-Ligand Docking 
PLoS ONE  2014;9(1):e85678.
Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1) filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2) monitoring job progress in real time, and 3) visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein-ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. istar is freely available at
PMCID: PMC3901662  PMID: 24475049
2.  Virtual screening studies reveal linarin as a potential natural inhibitor targeting CDK4 in retinoblastoma 
To find out whether linarin can be used as a potential natural inhibitor to target CDK4 in retinoblastoma using virtual screening studies.
Materials and Methods:
In this study, molecular modeling and protein structure optimization was performed for crystal structure of CDK4 (PDB id: 3G33), and was subjected to Molecular Dynamics (MD) simulation for 10 nanoseconds, as a preparatory process for docking. Furthermore, the stable conformation obtained in the MD simulation was utilized for virtual screening against the library of natural compounds in Indian Plant Anticancer Compounds Database (InPACdb) using AutoDock Vina. Finally, best docked ligands were revalidated individually through semi-flexible docking by AutoDock 4.0.
The CDK4 structure was stereochemically optimized to fix clashes and bad angles, which placed 96.4% residues in the core region of Ramachandran plot. The final structure of CDK4 that emerged after MD simulation was proven to be highly stable as per different validation tools. Virtual screening and docking was carried out for CDK4 against optimized ligands from InPACdb through AutoDock Vina. This inferred Linarin (Inpacdb AC.NO. acd0073) as a potential therapeutic agent with binding energy of -8.9 kJ/mol. Furthermore, it was also found to be valid as per AutoDock 4.0 semi-flexible docking procedure, with the binding energy of -8.18 kJ/mol and Ki value of 1.01 μM.
The docking results indicate linarin, a flavonoid plant compound, as a potential inhibitor of CDK4 compared to some of the currently practiced anticancer drugs for retinoblastoma. This finding can be extended to experimental validation to assess the in vivo efficacy of the identified compound.
PMCID: PMC3826001  PMID: 24250202
Cyclin-dependent kinase 4; InPACdb; molecular docking; molecular dynamics; retinoblastoma; virtual screening
3.  rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids 
PLoS Computational Biology  2014;10(4):e1003571.
Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrödinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at
PMCID: PMC3983074  PMID: 24722481
4.  Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines 
N-Acetylserotonin O-methyltransferase (ASMT) is an enzyme which by converting nor-melatonin to melatonin catalyzes the final reaction in melatonin biosynthesis in tryptophan metabolism pathway. High Expression of ASMT gene is evident in PPTs. The presence of abnormally high levels of ASMT in pineal gland could serve as an indication of the existence of pineal parenchymal tumors (PPTs) in the brain (J Neuropathol Exp Neurol 65: 675–684, 2006). Different levels of melatonin are used as a trait marker for prescribing the mood disorders e.g. Seasonal affective disorder, bipolar disorder, or major depressive disorder. In addition, melatonin levels can also be used to calculate the severity of a patient’s illness at a given point in time.
Seventy three melatoninergic inhibitors were docked with acetylserotonin-O-methyltransferase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking routines. Keeping this fact in view, critical evaluation of the performance of four different commonly used docking routines: AutoDock/Vina, GOLD, FlexX and FRED were performed. An evaluation criterion was based on the binding affinities/docking scores and experimental bioactivities.
Results and conclusion
Results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the compound selected as potent inhibitor is having minimum binding affinity, maximum GoldScore and minimum FlexX energy. The correlation value of r2 = 0. 66 may be useful in the selection of correct docked complexes based on the energy without having prior knowledge of the active site. This may lead to further understanding of structures, their reliability and Biomolecular activity especially in connection with bipolar disorders.
PMCID: PMC3819668  PMID: 24156411
Acetylserotonin-O-methyltransferase; Bipolar disorders; Pineal parenchymal tumors; Melatoninergic inhibitors; Molecular docking; Binding affinities
5.  MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters 
Virtual screening of small molecules using molecular docking has become an important tool in drug discovery. However, large scale virtual screening is time demanding and usually requires dedicated computer clusters. There are a number of software tools that perform virtual screening using AutoDock4 but they require access to dedicated Linux computer clusters. Also no software is available for performing virtual screening with Vina using computer clusters. In this paper we present MOLA, an easy-to-use graphical user interface tool that automates parallel virtual screening using AutoDock4 and/or Vina in bootable non-dedicated computer clusters.
MOLA automates several tasks including: ligand preparation, parallel AutoDock4/Vina jobs distribution and result analysis. When the virtual screening project finishes, an open-office spreadsheet file opens with the ligands ranked by binding energy and distance to the active site. All results files can automatically be recorded on an USB-flash drive or on the hard-disk drive using VirtualBox. MOLA works inside a customized Live CD GNU/Linux operating system, developed by us, that bypass the original operating system installed on the computers used in the cluster. This operating system boots from a CD on the master node and then clusters other computers as slave nodes via ethernet connections.
MOLA is an ideal virtual screening tool for non-experienced users, with a limited number of multi-platform heterogeneous computers available and no access to dedicated Linux computer clusters. When a virtual screening project finishes, the computers can just be restarted to their original operating system. The originality of MOLA lies on the fact that, any platform-independent computer available can he added to the cluster, without ever using the computer hard-disk drive and without interfering with the installed operating system. With a cluster of 10 processors, and a potential maximum speed-up of 10x, the parallel algorithm of MOLA performed with a speed-up of 8,64× using AutoDock4 and 8,60× using Vina.
PMCID: PMC2987878  PMID: 21029419
6.  Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock 
Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated.
The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method.
Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed.
Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.
PMCID: PMC2820493  PMID: 20150996
7.  Comparing Neural-Network Scoring Functions and the State of the Art: Applications to Common Library Screening 
We compare established docking programs, AutoDock Vina and Schrödinger’s Glide, to the recently published NNScore scoring functions. As expected, the best protocol to use in a virtual-screening project is highly dependent on the target receptor being studied. However, the mean screening performance obtained when candidate ligands are docked with Vina and rescored with NNScore 1.0 is not statistically different than the mean performance obtained when docking and scoring with Glide. We further demonstrate that the Vina and NNScore docking scores both correlate with chemical properties like small-molecule size and polarizability. Compensating for these potential biases leads to improvements in virtual screen performance. Composite NNScore-based scoring functions suited to a specific receptor further improve performance. We are hopeful that the current study will prove useful for those interested in computer-aided drug design.
PMCID: PMC3735370  PMID: 23734946
8.  Virtual Screening for HIV Protease Inhibitors: A Comparison of AutoDock 4 and Vina 
PLoS ONE  2010;5(8):e11955.
The AutoDock family of software has been widely used in protein-ligand docking research. This study compares AutoDock 4 and AutoDock Vina in the context of virtual screening by using these programs to select compounds active against HIV protease.
Methodology/Principal Findings
Both programs were used to rank the members of two chemical libraries, each containing experimentally verified binders to HIV protease. In the case of the NCI Diversity Set II, both AutoDock 4 and Vina were able to select active compounds significantly better than random (AUC = 0.69 and 0.68, respectively; p<0.001). The binding energy predictions were highly correlated in this case, with r = 0.63 and ι = 0.82. For a set of larger, more flexible compounds from the Directory of Universal Decoys, the binding energy predictions were not correlated, and only Vina was able to rank compounds significantly better than random.
In ranking smaller molecules with few rotatable bonds, AutoDock 4 and Vina were equally capable, though both exhibited a size-related bias in scoring. However, as Vina executes more quickly and is able to more accurately rank larger molecules, researchers should look to it first when undertaking a virtual screen.
PMCID: PMC2915912  PMID: 20694138
9.  Novel ligands that target the mitochondrial membrane protein mitoNEET 
Ligands of the thiazolidinedione (TZD) class of compounds, pioglitazone (Actos™) and rosiglitazone (Avandia™) are currently approved for treatment of type 2 diabetes and are known to bind to the PPAR-γ nuclear receptor subtype. Recent evidence suggesting PPAR-γ independent action of the TZDs led to the discovery of a novel integral outer mitochondrial membrane protein, mitoNEET. In spite of the several reported X-ray crystal structures of the unbound form of mitoNEET, the location and nature of the mitoNEET ligand binding sites (LBS) remain unknown. In this study, a molecular blind docking (BD) method was used to discover potential mitoNEET LBS and novel ligands, utilizing the program AutoDock Vina (v 1.0.2). Validation of BD was performed on the PPAR-γ receptor (PDB ID: 1ZGY) with the test compound rosiglitazone, demonstrating that the binding conformation of rosiglitazone determined by AutoDock Vina matches well with that of the cocrystallized ligand (root mean square deviation of the heavy atoms 1.45 Å). The locations and a general ligand binding interaction model for the LBS were determined, leading to the discovery of novel mitoNEET ligands. An in vitro fluorescence binding assay utilizing purified recombinant mitoNEET protein was used to determine the binding affinity of a predicted mitoNEET ligand, and the data obtained is in good agreement with AutoDock Vina results. The discovery of potential mitoNEET ligand binding sites and novel ligands, opens up the possibility for detailed structural studies of mitoNEET–ligand complexes, as well as rational design of novel ligands specifically targeted for mitoNEET.
PMCID: PMC3477874  PMID: 21531159
Mitoneet; Autodock; Docking; Fluorescence; Iron–sulfur; Thiazolidinedione
10.  Molecular docking between the RNA polymerase of the Moniliophthora perniciosa mitochondrial plasmid and Rifampicin produces a highly stable complex 
Moniliophthora perniciosa (Stahel) Aime & Phillips-Mora is the causal agent of witches’ broom disease (WBD) in cacao (Theobroma cacao). When the mitochondrial genome of this fungus had been completely sequenced, an integrated linear-type plasmid that encodes viral-like RNA polymerases was found. The structure of this polymerase was previously constructed using a homology modeling approach.
Using a virtual screening process, accessing the Kegg, PubChem and ZINC databases, we selected the eight most probable macrocyclic polymerase inhibitors to test against M. perniciosa RNA polymerase (RPO). AutoDock Vina was used to perform docking calculations for each molecule. This software returned affinity energy values for several ligand conformations. Subsequently, we used PyMOL 1.4 and Ligand Scout 3.1 to check the stereochemistry of chiral carbons, substructure, superstructure, number of rotatable bonds, number of rings, number of donor groups, and hydrogen bond receptors.
On the basis of this evidence we selected Rifampicin, a bacterial RNA polymerase inhibitor, and then AMBER 12 was used to simulate the behavior of the RPO-Rifampicin complex after a set of 5000 ps and up to 300 K in water. This calculation returned a graph of potential energy against simulation time and showed that the ligand remained inside the active site after the simulation was complete, with an average energy of -15 x 102 Kcal/Mol.
The results indicate that Rifampicin could be a good inhibitor for testing in vitro and in vivo against M. perniciosa.
PMCID: PMC3606170  PMID: 23442217
Moniliophthora perniciosa; RNA polymerase; Rifampicin; Docking; MM/PBSA
11.  Survey of public domain software for docking simulations and virtual screening 
Human Genomics  2011;5(5):497-505.
Progress in functional genomics and structural studies on biological macromolecules are generating a growing number of potential targets for therapeutics, adding to the importance of computational approaches for small molecule docking and virtual screening of candidate compounds. In this review, recent improvements in several public domain packages that are widely used in the context of drug development, including DOCK, AutoDock, AutoDock Vina and Screening for Ligands by Induced-fit Docking Efficiently (SLIDE) are surveyed. The authors also survey methods for the analysis and visualisation of docking simulations, as an important step in the overall assessment of the results. In order to illustrate the performance and limitations of current docking programs, the authors used the National Center for Toxicological Research (NCTR) oestrogen receptor benchmark set of 232 oestrogenic compounds with experimentally measured strength of binding to oestrogen receptor alpha. The methods tested here yielded a correlation coefficient of up to 0.6 between the predicted and observed binding affinities for active compounds in this benchmark.
PMCID: PMC3525969  PMID: 21807604
drug discovery; small molecule docking; virtual screening; docking packages; visualisation of docking poses; oestrogen receptor; oestrogen activity prediction; SAR
12.  Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge 
As part of the SAMPL4 blind challenge, filtered AutoDock Vina ligand docking predictions and large scale binding energy distribution analysis method binding free energy calculations have been applied to the virtual screening of a focused library of candidate binders to the LEDGF site of the HIV integrase protein. The computational protocol leveraged docking and high level atomistic models to improve enrichment. The enrichment factor of our blind predictions ranked best among all of the computational submissions, and second best overall. This work represents to our knowledge the first example of the application of an all-atom physics-based binding free energy model to large scale virtual screening. A total of 285 parallel Hamiltonian replica exchange molecular dynamics absolute protein-ligand binding free energy simulations were conducted starting from docked poses. The setup of the simulations was fully automated, calculations were distributed on multiple computing resources and were completed in a 6-weeks period. The accuracy of the docked poses and the inclusion of intramolecular strain and entropic losses in the binding free energy estimates were the major factors behind the success of the method. Lack of sufficient time and computing resources to investigate additional protonation states of the ligands was a major cause of mispredictions. The experiment demonstrated the applicability of binding free energy modeling to improve hit rates in challenging virtual screening of focused ligand libraries during lead optimization.
PMCID: PMC4137862  PMID: 24504704
Binding free energy; Reorganization free energy; Free energy ligand screening; BEDAM; HIV Integrase
13.  Binding Site and Affinity Prediction of General Anesthetics to Protein Targets Using Docking 
Anesthesia and Analgesia  2012;114(5):947-955.
The protein targets for general anesthetics remain unclear. A tool to predict anesthetic binding for potential binding targets is needed. In this study, we explore whether a computational method, AutoDock, could serve as such a tool.
High-resolution crystal data of water soluble proteins (cytochrome C, apoferritin and human serum albumin), and a membrane protein (a pentameric ligand-gated ion channel from Gloeobacter violaceus, GLIC) were used. Isothermal titration calorimetry (ITC) experiments were performed to determine anesthetic affinity in solution conditions for apoferritin. Docking calculations were performed using DockingServer with the Lamarckian genetic algorithm and the Solis and Wets local search method ( Twenty general anesthetics were docked into apoferritin. The predicted binding constants are compared with those obtained from ITC experiments for potential correlations. In the case of apoferritin, details of the binding site and their interactions were compared with recent co-crystallization data. Docking calculations for six general anesthetics currently used in clinical settings (isoflurane, sevoflurane, desflurane, halothane, propofol, and etomidate) with known EC50 were also performed in all tested proteins. The binding constants derived from docking experiments were compared with known EC50s and octanol/water partition coefficients for the six general anesthetics.
All 20 general anesthetics docked unambiguously into the anesthetic binding site identified in the crystal structure of apoferritin. The binding constants for 20 anesthetics obtained from the docking calculations correlate significantly with those obtained from ITC experiments (p=0.04). In the case of GLIC, the identified anesthetic binding sites in the crystal structure are among the docking predicted binding sites, but not the top ranked site. Docking calculations suggest a most probable binding site located in the extracellular domain of GLIC. The predicted affinities correlated significantly with the known EC50s for the six commonly used anesthetics in GLIC for the site identified in the experimental crystal data (p=0.006). However, predicted affinities in apoferritin, human serum albumin, and cytochrome C did not correlate with these six anesthetics’ known experimental EC50s. A weak correlation between the predicted affinities and the octanol/water partition coefficients was observed for the sites in GLIC.
We demonstrated that anesthetic binding sites and relative affinities can be predicted using docking calculations in an automatic docking server (Autodock) for both water soluble and membrane proteins. Correlation of predicted affinity and EC50 for six commonly used general anesthetics was only observed in GLIC, a member of a protein family relevant to anesthetic mechanism.
PMCID: PMC3334420  PMID: 22392968
14.  DockoMatic 2.0: High Throughput Inverse Virtual Screening and Homology Modeling 
DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly Graphical User Interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to: (1) conduct high throughput Inverse Virtual Screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying a receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories, and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELLER programs, and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education.
PMCID: PMC3916141  PMID: 23808933
15.  Potentially increasing the metabolic stability of drug candidates via computational site of metabolism prediction by CYP2C9: The utility of incorporating protein flexibility via an ensemble of structures 
Cytochrome P450 enzymes are responsible for metabolizing many endogenous and xenobiotic molecules encountered by the human body. It has been estimated that 75% of all drugs are metabolized by cytochrome P450 enzymes. Thus, predicting a compound s potential sites of metabolism (SOM) is highly advantageous early in the drug development process. We have combined molecular dynamics, AutoDock Vina docking, the neighboring atom type (NAT) reactivity model, and a solvent-accessible surface-area term to form a reactivity-accessibility model capable of predicting SOM for cytochrome P450 2C9 substrates. To investigate the importance of protein flexibility during the ligand binding process, the results of SOM prediction using a static protein structure for docking were compared to SOM prediction using multiple protein structures in ensemble docking. The results reported here indicate that ensemble docking increases the number of ligands that can be docked in a bioactive conformation (ensemble: 96%, static: 85%) but only leads to a slight improvement (49% vs. 44%) in predicting an experimentally known SOM in the top-1 position for a ligand library of 75 CYP2C9 substrates. Using ensemble docking, the reactivity-accessibility model accurately predicts SOM in the top-1 ranked position for 49% of the ligand library and considering the top-3 predicted sites increases the prediction success rate to approximately 70% of the ligand library. Further classifying the substrate library according to Km values leads to an improvement in SOM prediction for substrates with low Km values (57% at top-1). While the current predictive power of the reactivity-accessibility model still leaves significant room for improvement, the results illustrate the usefulness of this method to identify key protein-ligand interactions and guide structural modifications of the ligand to increase its metabolic stability.
PMCID: PMC3164910  PMID: 21703735
CYP2C9; metabolism; docking; protein flexibility; computational chemistry
16.  An Efficient Computational Method for Calculating Ligand Binding Affinities 
PLoS ONE  2012;7(8):e42846.
Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, the docking scores are not sufficiently precise to represent the protein-ligand binding affinity. Here, we developed an efficient computational method for calculating protein-ligand binding affinity, which is based on molecular mechanics generalized Born/surface area (MM-GBSA) calculations and Jarzynski identity. Jarzynski identity is an exact relation between free energy differences and the work done through non-equilibrium process, and MM-GBSA is a semimacroscopic approach to calculate the potential energy. To calculate the work distribution when a ligand is pulled out of its binding site, multiple protein-ligand conformations are randomly generated as an alternative to performing an explicit single-molecule pulling simulation. We assessed the new method, multiple random conformation/MM-GBSA (MRC-MMGBSA), by evaluating ligand-binding affinities (scores) for four target proteins, and comparing these scores with experimental data. The calculated scores were qualitatively in good agreement with the experimental binding affinities, and the optimal docking structure could be determined by ranking the scores of the multiple docking poses obtained by the molecular docking process. Furthermore, the scores showed a strong linear response to experimental binding free energies, so that the free energy difference of the ligand binding (ΔΔG) could be calculated by linear scaling of the scores. The error of calculated ΔΔG was within ≈±1.5 kcal•mol−1 of the experimental values. Particularly, in the case of flexible target proteins, the MRC-MMGBSA scores were more effective in ranking ligands than those generated by the MM-GBSA method using a single protein-ligand conformation. The results suggest that, owing to its lower computational costs and greater accuracy, the MRC-MMGBSA offers efficient means to rank the ligands, in the post-docking process, according to their binding affinities, and to compare these directly with the experimental values.
PMCID: PMC3423425  PMID: 22916168
17.  VitAL: Viterbi Algorithm for de novo Peptide Design 
PLoS ONE  2010;5(6):e10926.
Drug design against proteins to cure various diseases has been studied for several years. Numerous design techniques were discovered for small organic molecules for specific protein targets. The specificity, toxicity and selectivity of small molecules are hard problems to solve. The use of peptide drugs enables a partial solution to the toxicity problem. There has been a wide interest in peptide design, but the design techniques of a specific and selective peptide inhibitor against a protein target have not yet been established.
Methodology/Principal Findings
A novel de novo peptide design approach is developed to block activities of disease related protein targets. No prior training, based on known peptides, is necessary. The method sequentially generates the peptide by docking its residues pair by pair along a chosen path on a protein. The binding site on the protein is determined via the coarse grained Gaussian Network Model. A binding path is determined. The best fitting peptide is constructed by generating all possible peptide pairs at each point along the path and determining the binding energies between these pairs and the specific location on the protein using AutoDock. The Markov based partition function for all possible choices of the peptides along the path is generated by a matrix multiplication scheme. The best fitting peptide for the given surface is obtained by a Hidden Markov model using Viterbi decoding. The suitability of the conformations of the peptides that result upon binding on the surface are included in the algorithm by considering the intrinsic Ramachandran potentials.
The model is tested on known protein-peptide inhibitor complexes. The present algorithm predicts peptides that have better binding energies than those of the existing ones. Finally, a heptapeptide is designed for a protein that has excellent binding affinity according to AutoDock results.
PMCID: PMC2880006  PMID: 20532195
18.  Carborane Clusters in Computational Drug Design: A Comparative Docking Evaluation Using Autodock, Flexx, Glide and Surflex# 
Compounds containing boron atoms play increasingly important roles in the therapy and diagnosis of various diseases, particularly cancer. However, computational drug design of boron-containing therapeutics and diagnostics is hampered by the fact that many software packages used for this purpose lack parameters for all or part of the various types of boron atoms. In the present paper, we describe simple and efficient strategies to overcome this problem, which are based on the replacement of the boron atom types with carbon atom types. The developed methods were validated by docking closo- and nido-carboranyl antifolates into the active site of a human dihydrofolate reductase (hDHFR) using AutoDock, Glide, FlexX, and Surflex and comparing the obtained docking poses with the poses of their counterparts in the original hDHFR-carboranyl antifolate crystal structures. Under optimized conditions, AutoDock and Glide were equally good in docking of the closo-carboranyl antifolates followed by Surflex and FlexX whereas Autodock, Glide, and Surflex proved to be comparably efficient in the docking of nido-carboranyl antifolates followed by FlexX. Differences in geometries and partial atom charges in the structures of the carboranyl antifolates resulting from different data sources and/or optimization methods did not impact the docking performances of AutoDock or Glide significantly. Scoring functions generated by all four programs were in accordance with experimental data.
PMCID: PMC2702476  PMID: 19449853
Carboranes; Carboranyl Antifolates; Docking; Dihydrofolate Reductase; AutoDock; FlexX; Glide; Surflex
19.  Lessons Learned in Empirical Scoring with smina from the CSAR 2011 Benchmarking Exercise 
We describe a general methodology for designing an empirical scoring function and provide smina, a version of AutoDock Vina specially optimized to support high-throughput scoring and user-specified custom scoring functions. Using our general method, the unique capabilities of smina, a set of default interaction terms from AutoDock Vina, and the CSAR (Community Structure-Activity Resource) 2010 dataset, we created a custom scoring function and evaluated it in the context of the CSAR 2011 benchmarking exercise. We find that our custom scoring function does a better job sampling low RMSD poses when crossdocking compared to the default AutoDock Vina scoring function. The design and application of our method and scoring function reveal several insights into possible improvements and the remaining challenges when scoring and ranking putative ligands.
PMCID: PMC3726561  PMID: 23379370
20.  BSP-SLIM: A Blind Low-Resolution Ligand-Protein Docking Approach Using Predicted Protein Structures 
Proteins  2011;80(1):93-110.
We developed BSP-SLIM, a new method for ligand-protein blind docking using low-resolution protein structures. For a given sequence, protein structures are first predicted by I-TASSER; putative ligand binding sites are transferred from holo-template structures which are analogous to the I-TASSER models; ligand-protein docking conformations are then constructed by shape and chemical match of ligand with the negative image of binding pockets. BSP-SLIM was tested on 71 ligand-protein complexes from the Astex diverse set where the protein structures were predicted by I-TASSER with an average RMSD 2.92 Å on the binding residues. Using I-TASSER models, the median ligand RMSD of BSP-SLIM docking is 3.99 Å which is 5.94 Å lower than that by AutoDock; the median binding-site error by BSP-SLIM is 1.77 Å which is 6.23 Å lower than that by AutoDock and 3.43 Å lower than that by LIGSITECSC. Compared to the models using crystal protein structures, the median ligand RMSD by BSP-SLIM using I-TASSER models increases by 0.87 Å, while that by AutoDock increases by 8.41 Å; the median binding-site error by BSP-SLIM increase by 0.69 Å while that by AutoDock and LIGSITECSC increases by 7.31 Å and 1.41 Å, respectively. As case studies, BSP-SLIM was used in virtual screening for six target proteins, which prioritized actives of 25% and 50% in the top 9.2% and 17% of the library on average, respectively. These results demonstrate the usefulness of the template-based coarse-grained algorithms in the low-resolution ligand-protein docking and drug-screening. An on-line BSP-SLIM server is freely available at
PMCID: PMC3240723  PMID: 21971880
Blind ligand-protein docking; protein structure prediction; low-resolution docking
21.  Homology modeling and virtual screening approaches to identify potent inhibitors of VEB-1 β-lactamase 
blaVEB-1 is an integron-located extended-spectrum β-lactamase gene initially detected in Escherichia coli and Pseudomonas aeruginosa strains from south-east Asia. Several recent studies have reported that VEB-1-positive strains are highly resistant to ceftazidime, cefotaxime and aztreonam antibiotics. One strategy to overcome resistance involves administering antibiotics together with β-lactamase inhibitors during the treatment of infectious diseases. During this study, four VEB-1 β-lactamase inhibitors were identified using computer-aided drug design.
The SWISS-MODEL tool was utilized to generate three dimensional structures of VEB-1 β-lactamase, and the 3D model VEB-1 was verified using PROCHECK, ERRAT and VERIFY 3D programs. Virtual screening was performed by docking inhibitors obtained from the ZINC Database to the active site of the VEB-1 protein using AutoDock Vina software.
Results and conclusion
Homology modeling studies were performed to obtain a three-dimensional structure of VEB-1 β-lactamase. The generated model was validated, and virtual screening of a large chemical ligand library with docking simulations was performed using AutoDock software with the ZINC database. On the basis of the dock-score, four molecules were subjected to ADME/TOX analysis, with ZINC4085364 emerging as the most potent inhibitor of the VEB-1 β-lactamase.
PMCID: PMC3668210  PMID: 23547944
VEB-1 β-lactamase; Homology modeling; Virtual screening; Docking; Inhibitor
22.  NNScore 2.0: A Neural-Network Receptor–Ligand Scoring Function 
NNScore is a neural-network-based scoring function designed to aid the computational identification of small-molecule ligands. While the test cases included in the original NNScore article demonstrated the utility of the program, the application examples were limited. The purpose of the current work is to further confirm that neural-network scoring functions are effective, even when compared to the scoring functions of state-of-the-art docking programs, such as AutoDock, the most commonly cited program, and AutoDock Vina, thought to be two orders of magnitude faster. Aside from providing additional validation of the original NNScore function, we here present a second neural-network scoring function, NNScore 2.0. NNScore 2.0 considers many more binding characteristics when predicting affinity than does the original NNScore. The network output of NNScore 2.0 also differs from that of NNScore 1.0; rather than a binary classification of ligand potency, NNScore 2.0 provides a single estimate of the pKd. To facilitate use, NNScore 2.0 has been implemented as an open-source python script. A copy can be obtained from
PMCID: PMC3225089  PMID: 22017367
23.  AUDocker LE: A GUI for virtual screening with AUTODOCK Vina 
BMC Research Notes  2011;4:445.
AUTODOCK Vina is an open-source program which is steadfast and authentic to perform docking simulations. Though, Auto Dock Tools can help perform docking simulations with Vina, it largely remains as a platform for docking single molecule at a time.
"AUDocker LE" is designed with an aim to develop a software tool as a front end graphical interface with C# language to perform docking experiments in Windows based computers. It helps users to perform automated continuous docking of large ligand databases into a set of predefined protein targets. It will also help the user to analyze the results to select promising lead molecules.
AUDocker LE provides a straight forward graphical interface which can be used in a standard personal computer with Microsoft Windows XP or Windows 7 as the operating system where Autodock Vina, Python 2.5 and .net frame work are preinstalled.
PMCID: PMC3214202  PMID: 22026969
24.  Sliding Box Docking: a new stand-alone tool for managing docking-based virtual screening along the DNA helix axis 
Bioinformation  2013;9(14):750-751.
Sliding Box Docking is a program that manages simulations of ligand docking at different defined positions of a three-dimensional DNA structure. The procedure is similar to inverse docking, which is a method that performs docking simulations of a single ligand in the active sites of different targets. Sliding Box Docking manages docking simulations of one ligand into a box that slides along the DNA helix axis in regular steps. For each box position a score is calculated using the separate Autodock Vina software, and the results are automatically plotted. The evaluation of ligand interaction at different DNA locations can highlight the specificity of ligands for different DNA- sequences. When assessing the affinity between ligans AT base pairs, results for docking simulations with a test set that included berenil, distamycin, hoechst 33258, and netropsin were as expected, agreeing well with affinities previously described in the literature.
Binaries are freely available at
PMCID: PMC3746101  PMID: 23976834
DNA; Docking tools; software; docking manager
25.  Opal web services for biomedical applications 
Nucleic Acids Research  2010;38(Web Server issue):W724-W731.
Biomedical applications have become increasingly complex, and they often require large-scale high-performance computing resources with a large number of processors and memory. The complexity of application deployment and the advances in cluster, grid and cloud computing require new modes of support for biomedical research. Scientific Software as a Service (sSaaS) enables scalable and transparent access to biomedical applications through simple standards-based Web interfaces. Towards this end, we built a production web server ( in August 2007 to support the bioinformatics application called MEME. The server has grown since to include docking analysis with AutoDock and AutoDock Vina, electrostatic calculations using PDB2PQR and APBS, and off-target analysis using SMAP. All the applications on the servers are powered by Opal, a toolkit that allows users to wrap scientific applications easily as web services without any modification to the scientific codes, by writing simple XML configuration files. Opal allows both web forms-based access and programmatic access of all our applications. The Opal toolkit currently supports SOAP-based Web service access to a number of popular applications from the National Biomedical Computation Resource (NBCR) and affiliated collaborative and service projects. In addition, Opal’s programmatic access capability allows our applications to be accessed through many workflow tools, including Vision, Kepler, Nimrod/K and VisTrails. From mid-August 2007 to the end of 2009, we have successfully executed 239 814 jobs. The number of successfully executed jobs more than doubled from 205 to 411 per day between 2008 and 2009. The Opal-enabled service model is useful for a wide range of applications. It provides for interoperation with other applications with Web Service interfaces, and allows application developers to focus on the scientific tool and workflow development. Web server availability:
PMCID: PMC2896135  PMID: 20529877

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