Prediction of Multiple Binding Modes of the CDK2 Inhibitors, Anilinopyrazoles, Using the Automated Docking Programs GOLD, FlexX, and LigandFit: An Evaluation of Performance
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- 作者：Hideyuki Sato ; Lisa M. Shewchuk ; Jun Tang
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2006
- 出版时间：November 2006
- 年：2006
- 卷：46
- 期：6
- 页码：2552 - 2562
- 全文大小：683K
- 年卷期：v.46,no.6(November 2006)
- ISSN：1549-960X
文摘
Anilinopyrazoles as CDK2 inhibitors can adopt multiple binding modes depending on the substituents atthe 5-position of the pyrazole ring, based on CDK2/cyclin A crystallographic studies. Three commerciallyavailable docking programs, FlexX, GOLD, and LigandFit, were tested with 63 anilinopyrazole analoguesin an attempt to reproduce the binding modes observed in the crystal structures. Each docking programgave different ligand conformations depending on the scoring or energy functions used. FlexX/drugscore,GOLD/chemscore, and LigandFit/plp were the best combinations of each docking program in reproducingthe ligand conformations observed in the crystal structures. The 63 analogues were divided into two groups,type-A and type-B, depending on the substituent at the 5-position of the pyrazole ring. Although an alternatebinding mode, observed in a crystal structure of one type-B compound, could not be reproduced with anyof the above docking/scoring combinations, GOLD, with a template constraint based on the crystal structurecoordinates, was able to reproduce the pose. As for type-A compounds, all docking conditions yieldedsimilar poses to those observed in crystal structures. When predicting activities by scoring programs, thecombination of docking with LigandFit/plp and scoring with LIGSCORE1_CFF gave the best correlationcoefficient (r = 0.60) between experimental pIC50 values and top-ranked rescores of 30 poses of eachcompound. With regard to type-A compounds, the correlation was 0.69. However, when 11 compounds,whose top-ranked rescored poses did not demonstrate the correct binding modes in reference to the crystalstructure, were removed, the correlation rose to 0.75. Consequently, predicting activity on the basis of correctbinding modes was found to be reliable.