Identification of potential CDK 8 inhibitor from pyrimidine derivatives via In-Silico approach

Pyrimidinesare six-membered heterocyclic scaffold present naturally in nucleic acid components and are promising leads for the synthesis of medicinally important compounds. Cyclin-dependent kinases (CDKs) with a serine/threonine catalytic core are important druggable targets for cancer therapy and the binding of regulatory subunits controls them. In the present study series of virtually designed pyrimidine derivatives were screened using molecular docking techniques against the cyclin-dependent kinase-8 (CDK8) as a targeted protein. The density functional theory calculation of compounds having good binding affinity was done to estimate the orbital energy. The molecular dynamics simulation of the best-docked compound with the CDK8 was simulated to estimate the effect of mobility on the interactions.Themolecular docking provided insights regarding the binding ability of the designed compounds with the targeted CSK8 structure. As a result, the docked compounds exerted good interactions with the CDK8, and the compound PB129 showed the highest negative binding affinity of -12.4 kcal/mol with the formation of two hydrogen bonds. The results of the simulation study indicated that the complex of CDK-8 and PB129 hasa tight binding with constant hydrogen contacts. Moreover, the density functional theory indicated that PB129 has strong orbital energy and this compound will show tight interactions by either donating or accepting the electron with protein structure. Studied compounds showed good results for the docking study by exerting tight binding with the CDK-8 (PDB 6T41). Compound PB129 showed stable confirmation over the simulation run and has good orbital energies. Compound PB129 may act as a lead against the CDK8.