Enrichment of virtual hits by progressive shape-matching and docking.

The main applications of virtual chemical screening include the selection of a minimal receptor-relevant subset of a chemical library with a maximal chemical diversity. We have previously reported that the combination of ligand-centric and receptor-centric virtual screening methods may provide a compromise between computational time and accuracy during the hit enrichment process. In the present work, we propose a "progressive distributed docking" method that improves the virtual screening process using an iterative combination of shape-matching and docking steps. Known ligands with low docking scores were used as initial 3D templates for the shape comparisons with the chemical library. Next, new compounds with good template shape matches and low receptor docking scores were selected for the next round of shape searching and docking. The present iterative virtual screening process was tested for enriching peroxisome proliferator-activated receptor and phosphoinositide 3-kinase relevant compounds from a selected subset of the chemical libraries. It was demonstrated that the iterative combination improved the lead-hopping practice by improving the chemical diversity in the selected list of virtual hits.

[1]  Nanda Ghoshal,et al.  Combinatorial Library Enumeration and Lead Hopping using Comparative Interaction Fingerprint Analysis and Classical 2D QSAR Methods for Seeking Novel GABAA α3 Modulators , 2009, J. Chem. Inf. Model..

[2]  Robert J. Jilek,et al.  "Lead hopping". Validation of topomer similarity as a superior predictor of similar biological activities. , 2004, Journal of medicinal chemistry.

[3]  Andrew Smellie,et al.  Surrogate docking: structure-based virtual screening at high throughput speed , 2005, J. Comput. Aided Mol. Des..

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

[5]  Gisbert Schneider,et al.  Scaffold-hopping potential of fragment-based de novo design: the chances and limits of variation. , 2009, Combinatorial chemistry & high throughput screening.

[6]  Jürgen Bajorath,et al.  Virtual screening methods that complement HTS. , 2004, Combinatorial chemistry & high throughput screening.

[7]  Ruben Abagyan,et al.  Optimization of High Throughput Virtual Screening by Combining Shape‐Matching and Docking Methods. , 2008 .

[8]  Philip Prathipati,et al.  Global Bayesian Models for the Prioritization of Antitubercular Agents , 2008, J. Chem. Inf. Model..

[9]  Wei Li,et al.  Identifying Novel Molecular Structures for Advanced Melanoma by Ligand-Based Virtual Screening , 2009, J. Chem. Inf. Model..

[10]  Pierre Tufféry,et al.  Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity , 2009, BMC Bioinformatics.

[11]  David A. Cosgrove,et al.  Lead Hopping Using SVM and 3D Pharmacophore Fingerprints. , 2005 .

[12]  G. Klebe.  Virtual ligand screening: strategies, perspectives and limitations , 2006, Drug Discovery Today.

[13]  Bing Xiong,et al.  ScafBank: a public comprehensive Scaffold database to support molecular hopping , 2009, Acta Pharmacologica Sinica.

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

[15]  R. Mannhold,et al.  Multivariate analysis of experimental and computational descriptors of molecular lipophilicity , 1998, Journal of computer-aided molecular design.

[16]  Ajay N. Jain,et al.  Scoring functions for protein-ligand docking. , 2006, Current protein & peptide science.

[17]  J A McCammon,et al.  Accommodating protein flexibility in computational drug design. , 2000, Molecular pharmacology.

[18]  F. Petitet,et al.  Assessing the chemical diversity of an hsp90 database. , 2010, European journal of medicinal chemistry.

[19]  William J. Welsh,et al.  Identification of a Minimal Subset of Receptor Conformations for Improved Multiple Conformation Docking and Two-Step Scoring , 2004, J. Chem. Inf. Model..

[20]  T. Tuccinardi.  Docking-based virtual screening: recent developments. , 2009, Combinatorial chemistry & high throughput screening.

[21]  Ismael Zamora,et al.  SHOP: A Method For Structure‐Based Fragment and Scaffold Hopping , 2009, ChemMedChem.

[22]  Yvonne C. Martin,et al.  Application of Belief Theory to Similarity Data Fusion for Use in Analog Searching and Lead Hopping , 2008, J. Chem. Inf. Model..