Elucidation the binding mechanism of <i>Nelumbo nucifera</i>-derived isoquinoline alkaloids as Rho-kinase 1 inhibitors by molecular docking and dynamic simulation

Abstract

Rho-kinase 1 (ROCK1) is a key molecular target for controlling smooth muscle (SM) contraction in asthma, gastrointestinal disorders, hypertension. Embryos of lotus seed (Nelumbo nucifera) are traditional folk herbs widely used in treating various diseases which are closely related to SM contraction. With the aim of explaining the mechanism of embryos of lotus seed, 27 isoquinoline alkaloids were isolated from the embryos of lotus seed, the inhibitory activity of these alkaloids against ROCK1 were virtual screened via molecular docking and molecular dynamics (MD) simulations. The docking results indicated that 5 bisbenzylisoquinolines (BBIs) and 1 tribenzylisoquinoline (TBI) were potent inhibitors with high binding affinity for both A and B chains of ROCK1 (AcRock and BcRock). The MD results also revealed that neoliensinine (28) was the most potent inhibitor, which was corresponding to the irreversible relaxation effect of neoliensinine on SM. Moreover, through the MD simulation, it also indicated that neoliensinine (28) interacted in its stretched conformation through polar solvation interactions and van der Waal forces. Finally, with the best calculation results, the inhibition effect of neoliensinine (28) on the contraction of vascular smooth muscle cells (VSMCs) and ROCK1 was also confirmed by several biological tests.Communicated by Ramaswamy H. Sarma