Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Mahmoud A El Hassab,Amal Alharbi,Mohamed Fares,Mohammed K Abdel-Hamid Amin,Hamad M Alkahtani,Razan O Eskandrani,Sara T Al-Rashood,Wagdy M Eldehna

doi:10.3390/pr9061004

Abstract

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

Highlights

Emerging and neglected viral diseases are of immediate and critical societal importance as exemplified by the current COVID-19 pandemic
The employment of Fragment-Based Drug Design (FBDD) is based on three strategies: (a) fragment merging [25]
The main protease (Mpro) has a vital role in syndrome coronavirus (SARS)-CoV-2 replication by processing the polyprotein resulting from the RNA transcription into functioning units essential for virus replication, maturation and survival [10]

Summary

Introduction

Emerging and neglected viral diseases are of immediate and critical societal importance as exemplified by the current COVID-19 pandemic. The virus has been reported worldwide with more than 149 million confirmed cases and more than 3.1 million deaths as of February 2021. There is no specific antiviral drug for COVID-19 infection, and drug development and research have been limited to certain drug repurposing studies [1]. Despite the restrictions and safety measures that have been applied worldwide, the spread of the SARS-CoV-2 virus is still very hard to control, which highlights the urgent need to develop potent drugs against the virus. SARS-CoV-2 belongs to the coronavirus family, which is a single, positive-stranded RNA that is implicated in many human diseases, especially respiratory and neurological diseases [2]. The coronaviruses were the primary cause for two major outbreaks: in 2002, the severe acute respiratory syndrome coronavirus (SARS); and in 2012, the Middle East respiratory syndrome (MERS) [3,4]

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