Identification of Potent Angiotensin Converting Enzyme 2 Inhibitors through Virtual Screening and Structure-Based Pharmacophore Design

Authors: C Zozimus Divya Lobo, A Syed Mohamed, C Vedhi, S.V Rajesh, V Aroulmoji, Gnanendra Shanmugam,
Abstract: Angiotensin Converting Enzyme (ACE), a metallo-peptidase is the best known important drug target in the treatment of hypertension and responds to broad range ACE inhibitors such as Captopril. Whilst, many phytochemical compounds including alkaloids and flavonoids were also reported with anti-hypertensive activity. On the other hand, ACE2 is considered as an interesting new cardio-renal disease target as it is close and unique ACE homologue. In this scenario, the anti-hypertensive activities of 17 phytochemical compounds were analyzed through docking studies with ACE2. Also, the other ACE inhibitors with reported IC50 values were considered for docking interactions and used as training set. Further, the best docked phytochemical compound Rosemarinic acid and the training set compounds with ACE inhibitor activity were used to design the pharmacophore and validated. The generated 3D pharmacophore is subjected to screen the compounds with the significant chemical features against May bridged database consisting of more than one lakh compounds and subsequently, the hit compounds were screened using various filters such as estimated activity, Lipinski’s rule of five, and ADMET properties and resulted Eight compounds. The anti-hypertensive activities of these 5 compounds with good fit values were selected for further docking studies with ACE2. The five compounds PD 00533, CD 01374, CD 04888, CD 01278 and BTB 04932 exhibited the best docking scores and also favors the necessary hydrogen bond interactions with in the activity site of ACE and thus identified as novel leads with anti-hypertensive activity.