Repurposing potential of posaconazole and grazoprevir as inhibitors of SARS-CoV-2 helicase
Abidi S.H. Almansour N.M. Amerzhanov D. Allemailem K.S. Rafaqat W. Ibrahim M.A.A. la Fleur P. Lukac M. Ali S.
December 2021Nature Research
Scientific Reports
2021#11Issue 1
As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, − 54.8 and − 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.
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Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia
Nazarbayev University School of Medicine, Nazarbayev University, Astana, Kazakhstan
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
Medical College, Aga Khan University, Karachi, Pakistan
Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt
Department of Computer Science, School of Engineering and Digital Sciences, Nazarbayev University, Astana, Kazakhstan
Department of Biological and Biomedical Sciences
Department of Biology
Nazarbayev University School of Medicine
Department of Medical Laboratories
Medical College
Computational Chemistry Laboratory
Department of Computer Science
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