In silico design of novel CDK2 inhibitors through QSAR, ADMET, molecular docking and molecular dynamics simulation studies

The present study aims to investigate about the quantitative structure-activity relationship (QSAR) of a series of Thiazole derivatives reported as anticancer agents (hepatocellular carcinoma), using principally the electronic descriptors calculated by the DFT method and by applying the multiple linear regression method. The developed model showed good statistical parameters (R-2 = 0.725, R-adj(2) = 0.653, MSE = 0.060, R-test(2) = 0.827, Q(cv)(2) = 0.536). The energy EHOMO orbital, electronic energy (TE), shape coefficient (I), number of rotatable bonds (NROT), and index of refraction (n) were revealed to be the main descriptors influencing the anti-cancer activity. Further, new Thiazole derivatives have been designed and their activities and pharmacokinetic properties have been predicted using the validated QSAR model. The designed molecules were then assessed to molecular docking (MD), and molecular dynamic (MDs) simulation accompanied by the calculation of the binding affinity using MMPBSA script according to 100 ns a simulation trajectory, to study both their affinity and their stability towards CDK2 as a target protein for the cancer disease treatment. This research concluded with the identification of four new CDK2 inhibitors which are A1, A3, A5, and A6 showing good pharmacokinetic properties. The MDs results revealed that the newly designed compound A5 remained stable in the active center of the discovered CDK2 protein, indicating its potential as a novel inhibitor for the treatment of hepatocellular carcinoma. The current findings may eventually contribute to the development of robust CDK2 inhibitors in the future.Communicated by Ramaswamy H. Sarma