Prediction of multiple binding modes of the CDK2 inhibitors, anilinopyrazoles, using the automated docking programs GOLD, FlexX, and LigandFit: An evaluation of performance

Anilinopyrazoles as CDK2 inhibitors can adopt multiple binding modes depending on the substituents at the 5-position of the pyrazole ring, based on CDK2/cyclin A crystallographic studies. Three commercially available docking programs, FlexX, GOLD, and LigandFit, were tested with 63 anilinopyrazole analogues in an attempt to reproduce the binding modes observed in the crystal structures. Each docking program gave 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 reproducing the 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 alternate binding mode, observed in a crystal structure of one type-B compound, could not be reproduced with any of the above docking/scoring combinations, GOLD, with a template constraint based on the crystal structure coordinates, was able to reproduce the pose. As for type-A compounds, all docking conditions yielded similar poses to those observed in crystal structures. When predicting activities by scoring programs, the combination of docking with LigandFit/plp and scoring with LIGSCORE1_CFF gave the best correlation coefficient (r = 0.60) between experimental pIC(50) values and top-ranked rescores of 30 poses of each compound. 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 crystal structure, were removed, the correlation rose to 0.75. Consequently, predicting activity on the basis of correct binding modes was found to be reliable.