Identification of Main Protease of Coronavirus SARS-CoV-2 (Mpro) Inhibitors from Melissa officinalis

Abstract

Background: he recent outbreak of Coronavirus SARS-CoV-2 (Covid-19) which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. Compounds previously characterized from Melissa officinalis were queried against main protease of coronavirus SARS-CoV-2 using computational approach. Results: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_28 (R2 = 0.8548 and Q2=0.6474, and was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. Conclusion: Salvanolic acid A can be further evaluated as potential Mpro inhibitor.

Identification of lead compounds from large natural product library targeting 3C-like protease of SARS-CoV-2 using E-pharmacophore modelling, QSAR and molecular dynamics simulation

“…The protein crystal structure was prepared to assign bond orders and add missing hydrogen atoms. The protocol used has been well described in our previous computational studies (Iwaloye et al 2020b , c ). About sixty-nine thousand (69,000) compounds were retrieved from Natural product library (IBS Database, Inter Bio Screen Ltd, http://www.ibscreen.com/natural.shtml ) in SDF format, and prepared for docking using Ligprep (Schrödinger suites) and the procedure for preparation is detailed by Iwaloye et al ( 2020c ).…”

“…Compounds retrieved from natural products database were screened against a minimum of 3 sites from the five generated sites, and compounds with fitness score above the value of 1.0 were further filtered by molecular docking. Docking protocol was carried out by the method described in previous studies (Iwaloye et al 2020a , b ). Since the active site of SARS-CoV-2 3CLpro do not provide a medium of covalent interaction with any compound, all compounds experimented against SARS-CoV-2 3CLpro are non-covalent inhibitors.…”

“…These properties report energies for the ligand, receptor, and complex structures as well as energy differences relating to strain and binding, and are broken down into contributions from various terms in the energy expression. The Prime MM-GBSA calculates five fundamental energy which are optimized free receptor (= “ Receptor”), optimized free ligand (= “ Ligand”), optimized complex (= “ Complex”), receptor from minimized/optimized complex and ligand from minimized/optimized complex (Elekofehinti et al 2020a ).…”

“…Hence, identification of small molecules with the attribute of inhibiting replication mechanism of SARS-CoV-2 may serve as insight against COVID-19. In this direction, molecular docking and other computational procedures have proved valuable in the initial large-scale screening of several natural compounds and small molecules that directly inhibit essential target proteins (Elekofehinti et al 2020a , b ; Anand et al 2003 ).…”

Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2

“…Due to the crucial roles played by these proteases in the life cycle of the virus, they serve as prime targets for drug design. Recently published articles on COVID-19 employed the use of SARS-CoV-2 PLpro to screen drug-like compounds approved by the Federal Drug Agency (FDA) as novel inhibitors [23][24][25]. Hence, the present study exploited the same target (SARS-CoV-2 PLpro) to reveal potent anti-COVID-19 agents from a library of natural products.…”