Comparative binding affinity analysis of dual CDK2/FLT3 inhibitors

摘要

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 3H-pyrazolo 4,3-fquinoline 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.