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Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease.
J Biomol Struct Dyn. 2020 May 05 [Online ahead of print]JB

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (MPro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of MPro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae MPro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of MPro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 MPro. In agreement with this, we performed screening of ∼7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 MPro as the primary target. We identified several natural molecules like δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 MPro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.

Authors+Show Affiliations

Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India. Department of Botany, Savitribai Phule Pune University, Pune, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India.INTOX Private Limited, Pune, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32329408

Citation

Joshi, Rakesh S., et al. "Discovery of Potential Multi-target-directed Ligands By Targeting Host-specific SARS-CoV-2 Structurally Conserved Main Protease." Journal of Biomolecular Structure & Dynamics, 2020, pp. 1-16.
Joshi RS, Jagdale SS, Bansode SB, et al. Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease. J Biomol Struct Dyn. 2020.
Joshi, R. S., Jagdale, S. S., Bansode, S. B., Shankar, S. S., Tellis, M. B., Pandya, V. K., Chugh, A., Giri, A. P., & Kulkarni, M. J. (2020). Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease. Journal of Biomolecular Structure & Dynamics, 1-16. https://doi.org/10.1080/07391102.2020.1760137
Joshi RS, et al. Discovery of Potential Multi-target-directed Ligands By Targeting Host-specific SARS-CoV-2 Structurally Conserved Main Protease. J Biomol Struct Dyn. 2020 May 5;1-16. PubMed PMID: 32329408.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease. AU - Joshi,Rakesh S, AU - Jagdale,Shounak S, AU - Bansode,Sneha B, AU - Shankar,S Shiva, AU - Tellis,Meenakshi B, AU - Pandya,Vaibhav Kumar, AU - Chugh,Anita, AU - Giri,Ashok P, AU - Kulkarni,Mahesh J, Y1 - 2020/05/05/ PY - 2020/4/25/pubmed PY - 2020/4/25/medline PY - 2020/4/25/entrez KW - COVID-19 KW - Coronavirus KW - MPro KW - RdRp KW - SARS-CoV-2 virus KW - hACE-2 KW - multi-target-directed ligand KW - protease inhibitor SP - 1 EP - 16 JF - Journal of biomolecular structure & dynamics JO - J. Biomol. Struct. Dyn. N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in the current COVID-19 pandemic. Worldwide this disease has infected over 2.5 million individuals with a mortality rate ranging from 5 to 10%. There are several efforts going on in the drug discovery to control the SARS-CoV-2 viral infection. The main protease (MPro) plays a critical role in viral replication and maturation, thus can serve as the primary drug target. To understand the structural evolution of MPro, we have performed phylogenetic and Sequence Similarity Network analysis, that depicted divergence of Coronaviridae MPro in five clusters specific to viral hosts. This clustering was corroborated with the comparison of MPro structures. Furthermore, it has been observed that backbone and binding site conformations are conserved despite variation in some of the residues. These attributes can be exploited to repurpose available viral protease inhibitors against SARS-CoV-2 MPro. In agreement with this, we performed screening of ∼7100 molecules including active ingredients present in the Ayurvedic anti-tussive medicines, anti-viral phytochemicals and synthetic anti-virals against SARS-CoV-2 MPro as the primary target. We identified several natural molecules like δ-viniferin, myricitrin, taiwanhomoflavone A, lactucopicrin 15-oxalate, nympholide A, afzelin, biorobin, hesperidin and phyllaemblicin B that strongly binds to SARS-CoV-2 MPro. Intrestingly, these molecules also showed strong binding with other potential targets of SARS-CoV-2 infection like viral receptor human angiotensin-converting enzyme 2 (hACE-2) and RNA dependent RNA polymerase (RdRp). We anticipate that our approach for identification of multi-target-directed ligand will provide new avenues for drug discovery against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/32329408/Discovery_of_potential_multi_target_directed_ligands_by_targeting_host_specific_SARS_CoV_2_structurally_conserved_main_protease_ L2 - http://www.tandfonline.com/doi/full/10.1080/07391102.2020.1760137 DB - PRIME DP - Unbound Medicine ER -
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