<i>In Silico</i> Exploration of New Inhibitors of Protein Kinases Containing an N-Phenylbenzamide Linker: A Combination of Docking and Molecular Dynamics Modeling, Pharmacophore Modeling and Virtual Screening

Protein kinase inhibitors (PKIs) are widely used in the treatment of various human cancers. Still, their applications are limited by drug resistance (both intrinsic and acquired) and adverse toxicity. Beyond traditional design approaches, computational methods like pharmacophoric analysis, docking, and molecular dynamics have proven effective in PKI development. In this study, novel N-phenylbenzamide derivatives were designed as potential protein kinase inhibitors using the virtual combinatorial chemistry method guided by the pharmacophoric properties of approved PKIs. The antikinase activity of 25 studied structures was evaluated in silico using molecular docking and molecular dynamics protocols. Docking scores against 102 kinase receptors were obtained and benchmarked against reference ligands. MMPBSA binding energies were evaluated for the 36 most promising complexes in a series of 2 ns and 20 ns simulations. The results show that the designed structures are promising scaffolds for the development of new effective anticancer drugs.