Elucidating the Selective Mechanism of Drugs Targeting Cyclin-Dependent Kinases with Integrated MetaD-US Simulation

Cyclin-dependent kinases (CDKs), including CDK12 and
CDK13, play
crucial roles in regulating the cell cycle and RNA polymerase II activity,
making them vital targets for cancer therapies. SR4835 is a selective
inhibitor of CDK12/13, showing significant potential for treating
triple-negative breast cancer. To elucidate the selective mechanism
of SR4835 among three CDKs (CDK13/12/9), we developed an innovative
enhanced sampling method, integrated well-tempered metadynamics-umbrella
sampling (IMUS). IMUS synergistically combines the comprehensive pathway
exploration capability of well-tempered metadynamics (WT-MetaD) with
the precise free energy calculation capability of umbrella sampling,
enabling the efficient and accurate characterization of drug-target
interactions. The accurate calculation of binding free energy and
the detailed analysis of the kinetic mechanism of the drug-target
interaction using IMUS successfully elucidate the drug selectivity
mechanism targeting the three CDKs, showing that the selectivity is
primarily arising from differences in the stability of H-bonds within
the Hinge region of the kinases and the interaction patterns during
the protein–ligand recognition process. These findings also
underscore the utility of IMUS in efficiently and accurately capturing
drug-target interaction processes with clear mechanisms.