Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development.

Mohamed E Abouelela,Ahmed E El Zowalaty,Lassaad Belbahri,Mohamed Salaheldin A Abdelkader,Reda A Abdelhamid,Hamdy K Assaf,Ahmed M Sayed,Tomasz Oszako,Ehab S Elkhyat

doi:10.3390/molecules26061767

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.

Highlights

SARS-CoV-2, a novel coronavirus disease caused by Severe Acute Respiratory Syndrome Coronavirus 2, an RNA β-coronavirus, poses an increasing threat to human health
Structural and energetic analysis have shown that high-frequency contacts between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 spike protein lead to local conformational stability and large energetic cost was required for virus-cell collision at early stage facilitating cell entry [8,10,11].Coronavirus main protease (Mpro, known as 3CLpro), is the best characterized drug target, with no known human protease having the same cleavage pattern, so its inhibition leads to specific blockade of viral replication [12]
We conducted computational screening and molecular dynamics study on a library of isolated molecules from Aloe genus, investigated the binding affinity of these compounds with SARS-CoV-2 main protease (Mpro), spike glycoprotein (S) through molecular docking analysis

Summary

Introduction

SARS-CoV-2, a novel coronavirus disease caused by Severe Acute Respiratory Syndrome Coronavirus 2, an RNA β-coronavirus, poses an increasing threat to human health. Virtual screening and molecular modeling studies showed potential therapeutic activities of some natural products in inhibiting SARS-CoV-2 proteins including the main protease (Mpro), spike glycoprotein (S) and angiotensin converting enzyme-2 (ACE2) receptor which are promising potential therapeutic targets [22,27]. We conducted computational screening and molecular dynamics study on a library of isolated molecules from Aloe genus, investigated the binding affinity of these compounds with SARS-CoV-2 main protease (Mpro), spike glycoprotein (S) through molecular docking analysis. We conducted computational screening and molecular dynamics study on a library of isolated molecules from Aloe genus, investigated the binding affinity of these compounds 3wofit2h9 SARS-CoV-2 main protease (Mpro), spike glycoprotein (S) through molecular docking analysis. All compounds did not have predicted ability to pass the blood brain barrier (BBB) and are not expected to be neurotoxic

Phytochemical Review of Genus Aloe

Preparation of Ligand

Docking Analysis

Molecular Dynamics Simulation

Conclusions