COMPUTATIONAL DRUG REPROPOSING TO IDENTIFY SARS-COV-2 MPRO INHIBITORS: MOLECULAR DOCKING, ADMET ANALYSIS, AND  IN-SILICO/IN-VITRO TOXICITY STUDY

Mohammed Farrag El-Behairy; Marwa AA Fayed; Rasha M. Ahmed; Inas A. Abdallah

doi:10.22270/ujpr.v7i5.837

Mohammed Farrag El-Behairy Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.
Marwa AA Fayed Department of Pharmacognosy, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.
Rasha M. Ahmed Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
Inas A. Abdallah Department of Analytical Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.

10.22270/ujpr.v7i5.837

Keywords:

ADMET, Computational chemistry, fragment-based drug discovery, Simeprevir, COVID-19, Structure–activity relationships

Abstract

Aim and Objective: After the COVID-19 outbreak, drug repurposing has emerged as an effective and fast approach for combating the SARS-CoV-2 crisis. in this work, computational drug repurposing has been utilized to identify new SARS-CoV-2Mpro inhibitors.

Methods: Comparative molecular docking studies were used to evaluate the activity of the commercially available oral antiviral drug simeprevir and its degradation products (compounds 1–5) against the main protease (Mpro)of SARS-CoV-2 (PDB ID: 6lu7; resolution: 2.16 Å). Moreover, the ADMET and in-silico toxicity properties of the acidic (compounds 1–3) and oxidative (compounds 4 and 5) degradation products of simeprevir were predicted.

Results: Docking studies revealed good binding affinities for compounds (1–5) against Mpro of SARS-CoV-2, with binding free energies ranging from −6.23 to −7.65 kcal/mol. The acidic degradant 2 exhibited the best affinity and was superior to simeprevir and a natural ligand. All compounds were expected to be safe to the CNS.

Conclusion: Compounds 1, 4, and 5 were expected to possess good human intestinal absorption, whereas compounds 2 and 3 appeared to have moderate intestinal absorption.