Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.

Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments

Molecular docking has become an increasingly important tool for drug discovery. In this review, we present a brief introduction of the available molecular docking methods, and their development and applications in drug discovery. The relevant basic theories, including sampling algorithms and scoring functions, are summarized. The differences in and performance of available docking software are also discussed. Flexible receptor molecular docking approaches, especially those including backbone flexibility in receptors, are a challenge for available docking methods. A recently developed Local Move Monte Carlo (LMMC) based approach is introduced as a potential solution to flexible receptor docking problems. Three application examples of molecular docking approaches for drug discovery are provided.

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Molecular docking: a powerful approach for structure-based drug discovery.

Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature.

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Computational Methods in Drug Discovery

Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process.

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Structure-based virtual screening for drug discovery: principles, applications and recent advances.

As one of the most popular computational approaches in modern structure-based drug design, molecular docking can be used not only to identify the correct conformation of a ligand within the target binding pocket but also to estimate the strength of the interaction between a target and a ligand. Nowadays, as a variety of docking programs are available for the scientific community, a comprehensive understanding of the advantages and limitations of each docking program is fundamentally important to conduct more reasonable docking studies and docking-based virtual screening. In the present study, based on an extensive dataset of 2002 protein–ligand complexes from the PDBbind database (version 2014), the performance of ten docking programs, including five commercial programs (LigandFit, Glide, GOLD, MOE Dock, and Surflex-Dock) and five academic programs (AutoDock, AutoDock Vina, LeDock, rDock, and UCSF DOCK), was systematically evaluated by examining the accuracies of binding pose prediction (sampling power) and binding affinity estimation (scoring power). Our results showed that GOLD and LeDock had the best sampling power (GOLD: 59.8% accuracy for the top scored poses; LeDock: 80.8% accuracy for the best poses) and AutoDock Vina had the best scoring power (rp/rs of 0.564/0.580 and 0.569/0.584 for the top scored poses and best poses), suggesting that the commercial programs did not show the expected better performance than the academic ones. Overall, the ligand binding poses could be identified in most cases by the evaluated docking programs but the ranks of the binding affinities for the entire dataset could not be well predicted by most docking programs. However, for some types of protein families, relatively high linear correlations between docking scores and experimental binding affinities could be achieved. To our knowledge, this study has been the most extensive evaluation of popular molecular docking programs in the last five years. It is expected that our work can offer useful information for the successful application of these docking tools to different requirements and targets.

Comprehensive evaluation of ten docking programs on a diverse set of protein-ligand complexes: the prediction accuracy of sampling power and scoring power.

Molecular docking programs are widely used modeling tools for predicting ligand binding modes and structure based virtual screening. In this study, six molecular docking programs (DOCK, FlexX, GLIDE, ICM, PhDOCK, and Surflex) were evaluated using metrics intended to assess docking pose and virtual screening accuracy. Cognate ligand docking to 68 diverse, high-resolution X-ray complexes revealed that ICM, GLIDE, and Surflex generated ligand poses close to the X-ray conformation more often than the other docking programs. GLIDE and Surflex also outperformed the other docking programs when used for virtual screening, based on mean ROC AUC and ROC enrichment values obtained for the 40 protein targets in the Directory of Useful Decoys (DUD). Further analysis uncovered general trends in accuracy that are specific for particular protein families. Modifying basic parameters in the software was shown to have a significant effect on docking and virtual screening results, suggesting that expert knowledge is critical...

Comparison of several molecular docking programs: pose prediction and virtual screening accuracy.

Structure-based druggability assessment--identifying suitable targets for small molecule therapeutics.

Kinase hinge binding scaffolds and their hydrogen bond patterns

This work addresses the link between selectivity and an unusual, folded conformation for the P-loop observed initially for MAP4K4 and subsequently for other kinases. Statistical and computational analyses of our crystal structure database demonstrate that inhibitors that induce the P-loop folded conformation tend to be more selective, especially if they take advantage of this specific conformation by interacting more favorably with a conserved Tyr or Phe residue from the P-loop.

Understanding the Impact of the P-loop Conformation on Kinase Selectivity

We introduce a class of partial atomic charge assignment method that provides ab initio quality description of the electrostatics of bioorganic molecules. The method uses a set of models that neither have a fixed functional form nor require a fixed set of parameters, and therefore are capable of capturing the complexities of the charge distribution in great detail. Random Forest regression is used to build separate charge models for elements H, C, N, O, F, S, and Cl, using training data consisting of partial charges along with a description of their surrounding chemical environments; training set charges are generated by fitting to the b3lyp/6-31G* electrostatic potential (ESP) and are subsequently refined to improve consistency and transferability of the charge assignments. Using a set of 210 neutral, small organic molecules, the absolute hydration free energy calculated using these charges in conjunction with Generalized Born solvation model shows a low mean unsigned error, close to 1 kcal/mol, from the experimental data. Using another large and independent test set of chemically diverse organic molecules, the method is shown to accurately reproduce charge-dependent observables--ESP and dipole moment--from ab initio calculations. The method presented here automatically provides an estimate of potential errors in the charge assignment, enabling systematic improvement of these models using additional data. This work has implications not only for the future development of charge models but also in developing methods to describe many other chemical properties that require accurate representation of the electronic structure of the system.

Brajesh K. Rai

Papers

Comparison of several molecular docking programs: pose prediction and virtual screening accuracy.

Structure-based druggability assessment--identifying suitable targets for small molecule therapeutics.

Kinase hinge binding scaffolds and their hydrogen bond patterns

Understanding the Impact of the P-loop Conformation on Kinase Selectivity

Fast and accurate generation of ab initio quality atomic charges using nonparametric statistical regression