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      Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach

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          Abstract

          The SARS-CoV-2 pandemic has accelerated the study of existing drugs. The mixture of homologs called ivermectin (avermectin-B1a [HB1a] + avermectin-B1b [HB1b]) has shown antiviral activity against SARS-CoV-2 in vitro. However, there are few reports on the behavior of each homolog. We investigated the interaction of each homolog with promising targets of interest associated with SARS-CoV-2 infection from a biophysical and computational-chemistry perspective using docking and molecular dynamics. We observed a differential behavior for each homolog, with an affinity of HB1b for viral structures, and of HB1a for host structures considered. The induced disturbances were differential and influenced by the hydrophobicity of each homolog and of the binding pockets. We present the first comparative analysis of the potential theoretical inhibitory effect of both avermectins on biomolecules associated with COVID-19, and suggest that ivermectin through its homologs, has a multiobjective behavior.

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          A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

          David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou … (2020)
          SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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            Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

            Linlin Zhang, Daizong Lin, Xinyuanyuan Sun … (2020)
            The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, 3CLpro), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
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              The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

              Leon Caly, Julian Druce, Mike Catton … (2020)
              Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biophys Chem
                Journal ID (iso-abbrev): Biophys Chem
                Title: Biophysical Chemistry
                Publisher: Elsevier B.V.
                ISSN (Print): 0301-4622
                ISSN (Electronic): 1873-4200
                Publication date PMC-release: 19 August 2021
                Publication date (Print): November 2021
                Publication date (Electronic): 19 August 2021
                Volume: 278
                Page: 106677
                Affiliations
                [a ]Universidad del Zulia (LUZ), Facultad Experimental de Ciencias (FEC), Departamento de Biología, Laboratorio de Genética y Biología Molecular (LGBM), 4001 Maracaibo, Venezuela
                [b ]Instituto Venezolano de Investigaciones Científicas (IVIC), Centro de Estudios Botánicos y Agroforestales (CEBA), Laboratorio de Protección Vegetal (LPV), 4001 Maracaibo, Venezuela
                [c ]Instituto Venezolano de Investigaciones Científicas (IVIC), Centro de Investigación y Tecnología de Materiales (CITeMA), Laboratorio de Caracterización Molecular y Biomolecular, 4001 Maracaibo, Venezuela
                [d ]Facultad de Ciencias Naturales y Matemáticas, Departamento de Química y Ciencias Ambientales, Laboratorio de Análisis Químico Instrumental (LAQUINS), Escuela Superior Politécnica del Litoral, Guayaquil, Ecuador
                [e ]Departamento Académico de Química Analítica e Instrumental, Facultad de Química e Ingeniería Química, Universidad Nacional Mayor de San Marcos, Lima, Peru
                [f ]Departamento Académico de Química Inorgánica, Facultad de Química e Ingeniería Química, Universidad Nacional Mayor de San Marcos, Lima, Peru
                [g ]Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
                Author notes
                [* ]Correspondence to: Lenin González-Paz, LUZ-FEC. LGBM. Maracaibo 4001 – Zulia, Republica Bolivariana de Venezuela. IVIC- CEBA- LPV. Maracaibo 4001 – Zulia, Republica Bolivariana de Venezuela.
                [** ]Correspondence to: Ysaias J. Alvarado, Instituto Venezolano de Investigaciones Científicas (IVIC), Centro de Investigación y Tecnología de Materiales (CITeMA), Laboratorio de Caracterización Molecular y Biomolecular, Maracaibo, Republica Bolivariana de Venezuela
                Article
                Publisher Item ID: S0301-4622(21)00159-9 Publisher ID: 106677
                DOI: 10.1016/j.bpc.2021.106677
                PMC ID: 8373590
                PubMed ID: 34428682
                SO-VID: cea1e6c2-f5da-4ca2-89b4-eb389b44aede
                Copyright © © 2021 Elsevier B.V. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 29 April 2021
                Date revision received : 13 August 2021
                Date accepted : 15 August 2021
                Categories
                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Keywords: sars-cov-2,covid-19,molecular docking,molecular dynamic,ivermectin,avermectin
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: sars-cov-2, covid-19, molecular docking, molecular dynamic, ivermectin, avermectin

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