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Structure-based identification of potential SARS-CoV-2 main protease inhibitors.

Authors
  • Khan, Shama1
  • Fakhar, Zeynab2
  • Hussain, Afzal3
  • Ahmad, Aijaz1, 4
  • Jairajpuri, Deeba Shamim5
  • Alajmi, Mohamed F3
  • Hassan, Md Imtaiyaz6
  • 1 Department of Clinical Microbiology and Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. , (South Africa)
  • 2 Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa. , (South Africa)
  • 3 Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia. , (Saudi Arabia)
  • 4 National Health Laboratory Service, Infection Control, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa. , (South Africa)
  • 5 Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain. , (Bahrain)
  • 6 Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India. , (India)
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
May 01, 2022
Volume
40
Issue
8
Pages
3595–3608
Identifiers
DOI: 10.1080/07391102.2020.1848634
PMID: 33210561
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

To address coronavirus disease (COVID-19), currently, no effective drug or vaccine is available. In this regard, molecular modeling approaches are highly useful to discover potential inhibitors of the main protease (Mpro) enzyme of SARS-CoV-2. Since, the Mpro enzyme plays key roles in mediating viral replication and transcription; therefore, it is considered as an attractive drug target to control SARS-CoV-2 infection. By using structure-based drug design, pharmacophore modeling, and virtual high throughput drug screening combined with docking and all-atom molecular dynamics simulation approach, we have identified five potential inhibitors of SARS-CoV-2 Mpro. MD simulation studies revealed that compound 54035018 binds to the Mpro with high affinity (ΔGbind -37.40 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. We have identified promising leads to fight COVID-19 infection as these compounds fulfill all drug-likeness properties. However, experimental and clinical validations are required for COVID-19 therapy.Communicated by Ramaswamy H. Sarma.

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