Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases
General toxicity for the organism is a major drawback of anticancer drugs. Development of new generation chemotherapeutics requires the knowledge about macromolecules critical for tumor cell viability. Among these species (called therapeutic targets), the protein kinases are the established enzymes. However, the parts of protein kinases that are supposed to be targeted by drugs can be structurally similar. Therefore, it is difficult to design the compounds that selectively bind and inactivate individual kinases, especially if the proteins comprise the evolutionarily conserved families. In the present study, a set of advanced approaches of computational chemistry and biochemistry was used for the structure-based design of new compounds to inhibit cyclin-dependent protein kinases (CDK), the enzymes mechanistically implicated in tumor biology. We demonstrated the advantages of the non-equilibrium (NEQ) thermodynamics method for a time-efficacious, accurate, and informative prediction of CDK inhibitory properties of new compounds. Importantly, NEQ-based predictions correlated with experimental testing.