Structure-Based Virtual Screening, ADMET prediction and Molecular Dynamics simulation of isoindolin-1-one scaffolds as potential inhibitors of MNK2

Abstract

Mitogen-activated protein kinase 2 (MNK2) is a promising target for various types of cancers. It activates the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. Isoindolin-1-one scaffolds displayed significant anti-cancer activity as reported previously in research papers. In this study, we explored potential inhibition of various substituted isoindolin-1-one compounds against MNK2 through in silico studies. Structure-based virtual screening of a library of 180 compounds having isoindolin-1-one scaffold was done followed by fragment molecular orbital (FMO) calculations and molecular dynamics simulation (MDS) of the best two scored docked poses (compounds 132 and 160). The docking protocol was validated by superimposing the co-crystal ligand. Then, ADMET prediction of compounds 132 and 160 were performed. Sixteen compounds showed docking scores higher than or equal to co-crystal ligand of MNK2 protein and hydrogen bonding with MET162 residue. A 100 ns molecular dynamics simulation of compound 160 displayed excellent 95% hydrogen bond occupancy with MET162 residue of MNK2 protein showing remarkable docked pose stability throughout the simulation. Further, the ADMET prediction of compound 160 falls under the satisfactory range. Compound 160 exhibited potential inhibition against MNK2 protein. Thus, in silico studies of these isoindolin-1-ones will be helpful in the development of highly potent and selective MNK2 inhibitors.