Computational modeling of potential milciclib derivatives inhibitor-CDK2 binding through global docking and accelerated molecular dynamics simulations

Abstract

Hepatocellular carcinoma (HCC) is the most common malignant condition of the liver that occurs as a result of uncontrolled cellular proliferation after a series of disruptions at cell cycle regulatory checkpoints in the normal cell. Due to the lack of appropriate therapeutics or remedial treatment methods, new treatment strategies against HCC need to be developed. Cyclin dependent kinases (CDKs) are required to control the cell cycle and apoptosis, but their overexpressionis critical in the progression of cancer and is often expressed in HCC. Thus, CDKs are considered a promising class of target-defined therapy for HCC. Milciclib is a potential candidate for HCC which exhibits inhibitory activity against CDK2 leading to cell cycle arrest and apoptosis of tumor cells. Herein, we have halogenated the parent drug milciclib to improve its efficacy against CDK2. The primary structure of milciclib (D) was modified with F, Cl and,CF3 groups. The frontier molecular orbital features, binding affinity, non-bonded interaction and the pharmacokinetic parameters were analyzed for milciclib and its derivatives. We also performed molecular docking and extended molecular dynamics simulation studies to study the binding interactions and binding affinity more closely. Our computational investigation showed the derivatives D-F and D-CF3 have significant chemical reactivity, the best binding affinity, nonbonding interactions, and improved pharmacokinetic properties compared to the parent drug milciclib. Molecular dynamics analysis and MM-PBSA calculations indicated that D-Cl had a slightly more stable conformation and higher binding affinity compared to D-CF3.