Abstract

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved β-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket's crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand–protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC50 value of 0.030 μg ml−1. Besides, CAR was found to have a promising inhibitory activity with an IC50 of 0.350 μg ml−1. Also, the IC50 value of BIS was found to be as low as 15.917 μg ml−1. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC50 = 118.50, 204.60, and 60.20 μg ml−1, respectively) compared to lopinavir (IC50 = 73.68 μg ml−1) as a reference standard.

Highlights

  • The recent outbreak of novel corona virus pneumonia referred to as neo-coronary pneumonia caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in December 2019 raised global health concerns.[1]

  • The present study suggests the potential anti-SARS-CoV-2 activities of twenty b-adrenergic blockers containing the hydroxyethylamine and hydroxyethylene moieties

  • The SARS-CoV-2 Mpro inhibitory effects of the tested compounds (BIS, CAR, and NEB) were evaluated and the results showed very promising inhibitory activities (IC50 1⁄4 118.50, 204.60, and 60.20 mg mlÀ1, respectively) compared to lopinavir (IC50 1⁄4 73.68 mg mlÀ1) as a reference standard

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Summary

Introduction

The recent outbreak of novel corona virus pneumonia referred to as neo-coronary pneumonia caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in December 2019 raised global health concerns.[1]. Corona viruses are classi ed into four genera (a, b, g, and d). Severe acute respiratory syndrome-related coronavirus (SARSCoV), the Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 are b-coronaviruses.[7] Analysis of the genome sequences of these three viruses has revealed that SARS-CoV-2 has a higher identity to SARS-CoV (89.1% nucleotide similarity) than to MERS-CoV.[8] the SARS-CoV-2 genome is a single-stranded positive-sense RNA of about 30 kb in length and contains at least six open reading frames (ORFs) that code for a minimum of 16 non-structural proteins and 4 structural proteins.[9] The 229E gene encodes two polyproteins involved in releasing of functional polypeptides, and that are essential for viral replication and transcription. The protease responsible for the proteolytic processing is 3 chymotrypsin-like proteases of SARS-CoV-2 (3CLpro or Mpro), as it cleaves at least 11 sites on the polyproteins translated from the viral RNA.[10,11] Given the relevance for the viral replication cycle, the viral protease (Mpro) has been proven as an attractive target in the development of inhibitors against coronaviruses.[12,13,14,15,16,17,18,19]

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