A study of pyrazolo-benzimidazole derivatives as spleen tyrosine kinase inhibitors: an in-silico approach

Abstract

In an effort to contribute designing of improved anticancer molecules, in-silico prediction data including pharmacophore hypothesis, 3D-QSAR model, and molecular docking studies were performed on 55 compounds collected from literature. Tyrosine kinase has been used as a target enzyme as it plays a vital role in spleen cancer. The 3VF8 protein was selected for our molecular docking studies which is a crystal structure of spleen tyrosine kinase Syk catalytic domain with pyrazolylbenzimidazole inhibitor. A five-point pharmacophore was developed using 55 molecules having IC50 ranging from 13.2 to 0.83 μM. The best predictive pharmacophoric hypothesis ADRRR_2 was characterised by survival score 6.096, R2 = 0.8103, Q2 = 0.6169, F value = 20.3, RMSE = 0.45, Pearson-r = 0.4678, SD = 0.1905, and stability = 0.323 with a four-component PLS factor. In molecular docking studies, the compounds Bnz34, Bnz41, Bnz44, and Bnz45 showed interactions with MET448, LEU377, LEU307, LEU501, GLY378, LEU453, and LEU454 residues; these compounds have low-binding energies and a good in vivo activity. The pharmacophoric feature R5 is involved in hydrogen-bonding interaction whereas R7 is involved in aromatic hydrogen-bonding interactions with LEU377, GLY378, LEU501, LEU453, and LEU454 respectively. These results explained that one hydrogen acceptor, one hydrogen donor, and three aromatic rings are crucial for spleen tyrosine kinase inhibition.