Comparative binding affinity analysis of dual CDK2/FLT3 inhibitors

Abstract Selective inhibition of cyclin‐dependent kinase 2 (CDK2) using small molecules is gaining popularity for the treatment of certain types of acute myeloid leukemia (AML). In this study, we used different molecular modeling techniques to investigate the structure–activity relationship (SAR) and binding modalities of dual CDK2/FLT3 inhibitors. The key chemical characteristics of the 3 H ‐pyrazolo[4,3‐f]quinoline derivatives were highlighted as descriptive colored contours using comparative molecular similarity analysis (CoMSIA). Modifying chemical groups in existing compounds along these contours could improve CDK2 selectivity over FMS‐like tyrosine kinase 3 (FLT3). We determined the ligand affinities for CDK2 by estimating the binding free energy using molecular mechanics generalized Born surface area (MM‐GBSA) and umbrella sampling (US) simulations. Reasonable correlations were found between the computed and experimental binding energies, suggesting that MM‐GBSA and US can be used to reliably predict the binding affinities of new compounds in the more potent CDK2 drug development process.