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Citation
Tags
HERO ID
212262
Reference Type
Journal Article
Title
Lead finder: an approach to improve accuracy of protein-ligand docking, binding energy estimation, and virtual screening
Author(s)
Stroganov, OV; Novikov, FN; Stroylov, VS; Kulkov, V; Chilov, GG
Year
2008
Is Peer Reviewed?
Yes
Journal
Journal of Chemical Information and Modeling
ISSN:
1549-9596
Volume
48
Issue
12
Page Numbers
2371-2385
Language
English
DOI
10.1021/ci800166p
Abstract
An innovative molecular docking algorithm and three specialized high accuracy scoring functions are introduced in the Lead Finder docking software. Lead Finder's algorithm for ligand docking combines the classical genetic algorithm with various local optimization procedures and resourceful exploitation of the knowledge generated during docking process. Lead Finder's scoring functions are based on a molecular mechanics functional which explicitly accounts for different types of energy contributions scaled with empiric coefficients to produce three scoring functions tailored for (a) accurate binding energy predictions; (b) correct energy-ranking of docked ligand poses; and (c) correct rank-ordering of active and inactive compounds in virtual screening experiments. The predicted values of the free energy of protein-ligand binding were benchmarked against a set of experimentally measured binding energies for 330 diverse protein-ligand complexes yielding rmsd of 1.50 kcal/mol. The accuracy of ligand docking was assessed on a set of 407 structures, which included almost all published test sets of the following programs: FlexX, Glide SP, Glide XP, Gold, LigandFit, MolDock, and Surflex. rmsd of 2 A or less was observed for 80-96% of the structures in the test sets (80.0% on the Glide XP and FlexX test sets, 96.0% on the Surflex and MolDock test sets). The ability of Lead Finder to distinguish between active and inactive compounds during virtual screening experiments was benchmarked against 34 therapeutically relevant protein targets. Impressive enrichment factors were obtained for almost all of the targets with the average area under receiver operator curve being equal to 0.92.
Keywords
*Algorithms; Binding Sites; Databases, Protein; *Drug Evaluation, Preclinical/sn [Statistics & Numerical Data]; Ligands; *Proteins/ch [Chemistry]; *Proteins/me [Metabolism]; Software; Thermodynamics; *User-Computer Interface; 0 (Ligands); 0 (Proteins)
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