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Discovery of New Hydroxyethylamine Analogs against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure-Activity Relationship Studies.
Kumar, Sumit; Sharma, Prem Prakash; Shankar, Uma; Kumar, Dhruv; Joshi, Sanjeev K; Pena, Lindomar; Durvasula, Ravi; Kumar, Amit; Kempaiah, Prakasha; Rathi, Brijesh.
  • Kumar S; Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India.
  • Sharma PP; Laboratory for Translational Chemistry and Drug Discovery, Hansraj College, University of Delhi, Delhi 110007, India.
  • Shankar U; Descipline of Bioscience and Biomedical Engineering, Indian Institute of Technology, Indore, Simrol, Indore 453552, India.
  • Kumar D; Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida 201313, India.
  • Joshi SK; Technology Advisor, Defence Research & Development Organization, HQ, Rajaji Marg, New Delhi 110011, India.
  • Pena L; Department of Virology, Aggeu Magalhaes Institute (IAM), Oswaldo Cruz Foundation (Fiocruz), Recife, 50670-420 Pernambuco, Brazil.
  • Durvasula R; Department of Medicine, Loyola University Stritch School of Medicine, 2160 South First Avenue, Chicago, Illinois 60153, United States.
  • Kumar A; Descipline of Bioscience and Biomedical Engineering, Indian Institute of Technology, Indore, Simrol, Indore 453552, India.
  • Kempaiah P; Department of Medicine, Loyola University Stritch School of Medicine, 2160 South First Avenue, Chicago, Illinois 60153, United States.
  • Poonam; Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India.
  • Rathi B; Laboratory for Translational Chemistry and Drug Discovery, Hansraj College, University of Delhi, Delhi 110007, India.
J Chem Inf Model ; 60(12): 5754-5770, 2020 12 28.
Article in English | MEDLINE | ID: covidwho-526060
ABSTRACT
The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (Mpro) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CLpro), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CLpro) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound 16 with a docking score of -8.955 adhered to drug-like parameters, and the structure-activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of 16 within the binding pocket. Largely, our results supported that this novel compound 16 binds with domains I and II, and the domain II-III linker of the 3CLpro protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Ethanolamines / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: J Chem Inf Model Journal subject: Medical Informatics / Chemistry Year: 2020 Document Type: Article Affiliation country: Acs.jcim.0c00326

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Ethanolamines / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: J Chem Inf Model Journal subject: Medical Informatics / Chemistry Year: 2020 Document Type: Article Affiliation country: Acs.jcim.0c00326