Use of Experimental Design To Optimize Docking Performance: The Case of LiGenDock, the Docking Module of Ligen, a New De Novo Design Program

On route toward a novel de novo design program, called LiGen, we developed a docking program, LiGenDock, based on pharmacophore models of binding sites, including a non-enumerative docking algorithm. In this paper, we present the functionalities of LiGenDock and its accompanying module LiGenPocket, aimed at the binding site analysis and structure-based pharmacophore definition. We also report the optimization procedure we have carried out to improve the cognate docking and virtual screening performance of LiGenDock. In particular, we applied the design of experiments (DoE) methodology to screen the set of user-adjustable parameters to identify those having the largest influence on the accuracy of the results (which ensure the best performance in pose prediction and in virtual screening approaches) and then to choose their optimal values. The results are also compared with those obtained by two popular docking programs, namely, Glide and AutoDock for pose prediction, and Glide and DOCK6 for Virtual Screening.

[1]  Renxiao Wang,et al.  The PDBbind database: methodologies and updates. , 2005, Journal of medicinal chemistry.

[2]  Maria Kontoyianni,et al.  Evaluation of docking performance: comparative data on docking algorithms. , 2004, Journal of medicinal chemistry.

[3]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[4]  J. Bajorath,et al.  Docking and scoring in virtual screening for drug discovery: methods and applications , 2004, Nature Reviews Drug Discovery.

[5]  Andreas Bender,et al.  Recognizing Pitfalls in Virtual Screening: A Critical Review , 2012, J. Chem. Inf. Model..

[6]  C. David Andersson,et al.  A Multivariate Approach to Investigate Docking Parameters' Effects on Docking Performance , 2007, J. Chem. Inf. Model..

[7]  Ajay N. Jain.  Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. , 2003, Journal of medicinal chemistry.

[8]  Christopher I. Bayly,et al.  Evaluating Virtual Screening Methods: Good and Bad Metrics for the "Early Recognition" Problem , 2007, J. Chem. Inf. Model..

[9]  Petra Schneider,et al.  Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia , 2011, PloS one.

[10]  Ruth Nussinov,et al.  Principles of docking: An overview of search algorithms and a guide to scoring functions , 2002, Proteins.

[11]  Carlo Cavazzoni,et al.  LiGen: A High Performance Workflow for Chemistry Driven de Novo Design , 2013, J. Chem. Inf. Model..

[12]  Pedro Alexandrino Fernandes,et al.  Protein–ligand docking: Current status and future challenges , 2006, Proteins.

[13]  Ruben Abagyan,et al.  ICM—A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation , 1994, J. Comput. Chem..

[14]  M. Bezerra,et al.  Response surface methodology (RSM) as a tool for optimization in analytical chemistry. , 2008, Talanta.

[15]  Renxiao Wang,et al.  The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures. , 2004, Journal of medicinal chemistry.

[16]  Aniko Simon,et al.  eHiTS: an innovative approach to the docking and scoring function problems. , 2006, Current protein & peptide science.

[17]  Sudipto Mukherjee,et al.  Evaluation of DOCK 6 as a pose generation and database enrichment tool , 2012, Journal of Computer-Aided Molecular Design.

[18]  F. Massey.  The Kolmogorov-Smirnov Test for Goodness of Fit , 1951 .

[19]  Ruben Abagyan,et al.  Comparative study of several algorithms for flexible ligand docking , 2003, J. Comput. Aided Mol. Des..

[20]  Richard A. Friesner,et al.  Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide , 2012, Journal of Computer-Aided Molecular Design.

[21]  Yongbo Hu,et al.  Comparison of Several Molecular Docking Programs: Pose Prediction and Virtual Screening Accuracy , 2009, J. Chem. Inf. Model..

[22]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[23]  Kenji Onodera,et al.  Evaluations of Molecular Docking Programs for Virtual Screening , 2007, J. Chem. Inf. Model..

[24]  Natasja Brooijmans,et al.  Molecular recognition and docking algorithms. , 2003, Annual review of biophysics and biomolecular structure.

[25]  Robin Taylor,et al.  A new test set for validating predictions of protein–ligand interaction , 2002, Proteins.

[26]  Ajay N. Jain,et al.  Recommendations for evaluation of computational methods , 2008, J. Comput. Aided Mol. Des..

[27]  J. A. Grant,et al.  Gaussian docking functions. , 2003, Biopolymers.

[28]  Luhua Lai,et al.  LigBuilder: A Multi-Purpose Program for Structure-Based Drug Design , 2000 .

[29]  Colin McMartin,et al.  QXP: Powerful, rapid computer algorithms for structure-based drug design , 1997, J. Comput. Aided Mol. Des..

[30]  Thomas Lengauer,et al.  POEM: Parameter Optimization Using Ensemble Methods: Application to Target Specific Scoring Functions , 2005, J. Chem. Inf. Model..

[31]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[32]  I. Kuntz,et al.  Matching chemistry and shape in molecular docking. , 1993, Protein engineering.

[33]  T. Lundstedt,et al.  Experimental design and optimization , 1998 .

[34]  Luhua Lai,et al.  Further development and validation of empirical scoring functions for structure-based binding affinity prediction , 2002, J. Comput. Aided Mol. Des..

[35]  Dariusz Plewczynski,et al.  Can we trust docking results? Evaluation of seven commonly used programs on PDBbind database , 2011, J. Comput. Chem..

[36]  J. Irwin,et al.  Benchmarking sets for molecular docking. , 2006, Journal of medicinal chemistry.

[37]  Walter Filgueira de Azevedo,et al.  Molecular docking algorithms. , 2008, Current drug targets.

[38]  Zhihai Liu,et al.  Evaluation of the performance of four molecular docking programs on a diverse set of protein‐ligand complexes , 2010, J. Comput. Chem..

[39]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.