Journal of Computer-Aided Molecular Design

, Volume 26, Issue 6, pp 725–735

Lead Finder docking and virtual screening evaluation with Astex and DUD test sets

  • Fedor N. Novikov
  • Viktor S. Stroylov
  • Alexey A. Zeifman
  • Oleg V. Stroganov
  • Val Kulkov
  • Ghermes G. Chilov
Article

Abstract

Lead Finder is a molecular docking software. Sampling uses an original implementation of the genetic algorithm that involves a number of additional optimization procedures. Lead Finder’s scoring functions employ a set of semi-empiric molecular mechanics functionals that have been parameterized independently for docking, binding energy predictions and rank-ordering for virtual screening. Sampling and scoring both utilize a staged approach, moving from fast but less accurate algorithm versions to computationally more intensive but more accurate versions. Lead Finder includes tools for the preparation of full atom protein and ligand models. In this exercise, Lead Finder achieved 72.9% docking success rate on the Astex test set when the original author-prepared full atom models were used, and 74.1% success rate when the structures were prepared by Lead Finder. The major cause of docking failures were scoring errors resulting from the use of imperfect solvation models. In many cases, docking errors could be corrected by the proper protonation and the use of correct cyclic conformations of ligands. In virtual screening experiments on the DUD test set the early enrichment factor of several tens was achieved on average. However, the area under the ROC curve (“AUC ROC”) ranged from 0.70 to 0.74 depending on the screening protocol used, and the separation from the null model was not perfect—0.12–0.15 units of AUC ROC. We assume that effective virtual screening in the whole range of enrichment curve and not just at the early enrichment stages requires more accurate solvation modeling and accounting for the protein backbone flexibility.

Keywords

Lead Finder Docking Virtual screening Benchmarks Astex DUD 

Supplementary material

10822_2012_9549_MOESM1_ESM.doc (280 kb)
Supplementary material 1 (DOC 280 kb)

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Fedor N. Novikov
    • 1
  • Viktor S. Stroylov
    • 1
  • Alexey A. Zeifman
    • 2
  • Oleg V. Stroganov
    • 1
    • 2
  • Val Kulkov
    • 3
  • Ghermes G. Chilov
    • 1
    • 2
  1. 1.MolTech LtdMoscowRussia
  2. 2.N.D.Zelinsky Institute of Organic ChemistryMoscowRussia
  3. 3.BioMolTech CorpTorontoCanada

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