Triazole based isatin derivatives as potential inhibitor of key cancer promoting kinases- insight from electronic structure, docking and molecular dynamics simulations.

Computer Aided Drug Design approaches have been applied to predict potential inhibitors for two different kinases, namely, cyclin-dependent kinase 2 (CDK2) and Epidermal Growth Factor Receptor (EGFR) which are known to play crucial role in cancer growth. We have designed alkyl and aryl substituted isatin-triazole ligands and performed molecular docking to rank and predict possible binding pockets in CDK2 and EGFR kinases. Best-scoring ligands in the kinase-binding pocket were selected from the docking study and subjected to molecular dynamics simulation. Absolute binding affinities were estimated from the MD trajectories using the MM/PBSA approach. The results suggest that aryl substituted isatin-triazole ligands are better binder to the kinases relative to its alkyl analogue. Furthermore, aryl substituted isatin-triazole ligands prefer binding to EGFR kinases relative to CDK2. The ligand binding pockets of the kinases are primarily hydrophobic in nature. Ligand-kinase binding is favoured by electrostatic and Van der Waals interactions, later being the major contributor. Large estimated negative binding affinities (~ -10 to -25 kcal/mol) indicate that the ligands might inhibit the kinases. Physicochemical property analysis suggests that the proposed ligands could be orally bio-available.