Keywords
CDK7 inhibitors
cyclin-dependent kinase 7
free energy perturbation
hepatotoxicity
molecular dynamics
non-hepatotoxic scaffold
PHA-793887
relative binding free energy
Abstract
Although CDK7 inhibitors are considered to be potential anticancer drugs, all inhibitors developed so far have significant disadvantages preventing their further use. We have developed a new CDK7 inhibitor scaffold lacking hepatotoxicity using molecular dynamics (MD) and free energy perturbation (FEP/MD) methods, and were able to double its binding affinity after additional research. The combination of MD and FEP/MD methods was shown to be a valuable instrument for the development of novel and potent CDK7 inhibitors for anticancer therapy.
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