Pharmacophore-Based Virtual Screening, Quantum Mechanics Calculations, and Molecular Dynamics Simulation Approaches Identified Potential Natural Antiviral Drug Candidates against MERS-CoV S1-NTD.

Thamer A Bouback,Sushil Pokhrel,Rahat Alam,Md Saddam Hossen,Abdus Samad,Md Enamul Kabir Talukder,Amal Mohammed Aljohani,Foysal Ahammad,Ishtiaq Qadri,Abdulaziz Albeshri,Jesus Simal-Gandara,Khalid Al-Ghamdi

doi:10.3390/molecules26164961

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >−9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.

Highlights

Coronavirus (CoVs) is a member of the family Coronaviridae, containing a singlestranded positive-sense RNA genome [+ssRNA] that has a length between ~27 kb to 32 kb
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Summary

Introduction

Coronavirus (CoVs) is a member of the family Coronaviridae, containing a singlestranded positive-sense RNA genome [+ssRNA] that has a length between ~27 kb to 32 kb. Four common human coronaviruses (HCoVs) NL63 and 229E (α-CoVs); OC43 and HKU1 (β-CoVs) circulate widely in the human population, each capable of causing severe disease ranging from common colds to self-limiting upper respiratory infections in immunocompetent people. Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, and MERSCoV are other known human beta CoVs (β-CoVs) capable of causing epidemics [3,4]. They are zoonotic in characters and infections with the virus resulting in various clinical severity featuring respiratory and extra-respiratory manifestations [5]. MERS-CoV has the highest fatality rate in humans and animals, but effective antiviral candidates are not available to treat the infection caused by the pathogen

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Conclusion