Can we use docking and scoring for hit-to-lead optimization?
- 9 January 2008
- journal article
- Published by Springer Nature in Journal of Computer-Aided Molecular Design
- Vol. 22 (3-4) , 161-168
- https://doi.org/10.1007/s10822-007-9165-4
Abstract
Docking and scoring is currently one of the tools used for hit finding and hit-to-lead optimization when structural information about the target is known. Docking scores have been found useful for optimizing ligand binding to reproduce experimentally observed binding modes. The question is, can docking and scoring be used reliably for hit-to-lead optimization? To illustrate the challenges of scoring for hit-to-lead optimization, the relationship of docking scores with experimentally determined IC50 values measured in-house were tested. The influences of the particular target, crystal structure, and the precision of the scoring function on the ability to differentiate between actives and inactives were analyzed by calculating the area under the curve of receiver operator characteristic curves for docking scores. It was found that for the test sets considered, MW and sometimes ClogP were as useful as GlideScores and no significant difference was observed between SP and XP scores for differentiating between actives and inactives. Interpretation by an expert is still required to successfully utilize docking and scoring in hit-to-lead optimization.Keywords
This publication has 47 references indexed in Scilit:
- Comparative Performance of Several Flexible Docking Programs and Scoring Functions: Enrichment Studies for a Diverse Set of Pharmaceutically Relevant TargetsJournal of Chemical Information and Modeling, 2007
- Ensemble Modeling of Substrate Binding to Cytochromes P450: Analysis of Catalytic Differences between CYP1A Orthologs,Biochemistry, 2007
- Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase InhibitorJournal of Medicinal Chemistry, 2007
- Surface comparison of active and inactive protein kinases identifies a conserved activation mechanismProceedings of the National Academy of Sciences, 2006
- Structure modeling, ligand binding, and binding affinity calculation (LR‐MM‐PBSA) of human heparanase for inhibition and drug designProteins-Structure Function and Bioinformatics, 2006
- Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitorsBioorganic & Medicinal Chemistry Letters, 2005
- Validation of Molecular Docking Calculations Involving FGF-1 and FGF-2Journal of Medicinal Chemistry, 2004
- Discovery of Small-Molecule Inhibitors of Bcl-2 through Structure-Based Computer ScreeningJournal of Medicinal Chemistry, 2001
- The Protein Data BankNucleic Acids Research, 2000
- Semianalytical treatment of solvation for molecular mechanics and dynamicsJournal of the American Chemical Society, 1990