Identification of natural inhibitors against angiotensin I converting enzyme for cardiac safety using induced fit docking and MM‑GBSA studies

Background: Cleistanthins A and B are isolated compounds from the leaves of Cleistanthus collinus Roxb (Euphorbiaceae). This plant is poisonous in nature which causes cardiovascular abnormalities such as hypotension, nonspecific ST‑T changes and QTc prolongation. The biological activity predictions spectra of the compounds show the presence of antihypertensive, diuretic and antitumor activities. Objective: Objective of the present study was to determine the in silico molecular interaction of cleistanthins A and B with Angiotensin I‑ Converting Enzyme (ACE‑I) using Induced Fit Docking (IFD) protocols. Materials and Methods: All the molecular modeling calculations like IFD docking, binding free energy calculation and ADME/Tox were carried out using Glide software (Schrödinger LLC 2009, USA) in CentOS EL‑5 workstation. Results: The IFD complexes showed favorable docking score, glide energy, glide emodel, hydrogen bond and hydrophobic interactions between the active site residues of ACE‑I and the compounds. Binding free energy was calculated for the IFD complexes using Prime MM‑GBSA method. The conformational changes induced by the inhibitor at the active site of ACE‑I were observed based on changes of the back bone Cα atoms and side‑chain chi (x) angles. The various physicochemical properties were calculated for these compounds. Both cleistanthins A and B showed better docking score, glide energy and glide emodel when compared to captopril inhibitor. Conclusion: These compounds have successively satisfied all the in silico parameters and seem to be potent inhibitors of ACE‑I and potential candidates for hypertension.