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Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms.
Quimque, Mark Tristan J; Notarte, Kin Israel R; Fernandez, Rey Arturo T; Mendoza, Mark Andrew O; Liman, Rhenz Alfred D; Lim, Justin Allen K; Pilapil, Luis Agustin E; Ong, Jehiel Karsten H; Pastrana, Adriel M; Khan, Abbas; Wei, Dong-Qing; Macabeo, Allan Patrick G.
  • Quimque MTJ; Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines.
  • Notarte KIR; The Graduate School, University of Santo Tomas, Manila, Philippines.
  • Fernandez RAT; Chemistry Department, College of Science and Mathematics, Mindanao State University - Iligan Institute of Technology, Tibanga, Iligan City, Philippines.
  • Mendoza MAO; Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines.
  • Liman RAD; Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines.
  • Lim JAK; Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines.
  • Pilapil LAE; The Graduate School, University of Santo Tomas, Manila, Philippines.
  • Ong JKH; Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines.
  • Pastrana AM; Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines.
  • Khan A; Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines.
  • Wei DQ; Faculty of Medicine and Surgery, University of Santo Tomas, Manila, Philippines.
  • Macabeo APG; Department of Bioinformatics and Biostatistics, State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, China.
J Biomol Struct Dyn ; 39(12): 4316-4333, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1317837
ABSTRACT
The novel coronavirus SARS-CoV2, the causative agent of the pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide necessitated the discovery of new substances for anti-COVID-19 drug development. With the aid of bioinformatics and computational modelling, ninety seven antiviral secondary metabolites from fungi were docked onto five SARS-CoV2 enzymes involved in viral attachment, replication, post-translational modification, and host immunity evasion infection mechanisms followed by molecular dynamics simulation and in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, three fumiquinazoline alkaloids scedapin C (15), quinadoline B (19) and norquinadoline A (20), the polyketide isochaetochromin D1 (8), and the terpenoid 11a-dehydroxyisoterreulactone A (11) exhibited high binding affinities on the target proteins, papain-like protease (PLpro), chymotrypsin-like protease (3CLpro), RNA-directed RNA polymerase (RdRp), non-structural protein 15 (nsp15), and the spike binding domain to GRP78. Molecular dynamics simulation was performed to optimize the interaction and investigate the stability of the top-scoring ligands in complex with the five target proteins. All tested complexes were found to have dynamic stability. Of the five top-scoring metabolites, quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.Communicated by Ramaswamy H. Sarma.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: J Biomol Struct Dyn Year: 2021 Document Type: Article Affiliation country: 07391102.2020.1776639

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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: J Biomol Struct Dyn Year: 2021 Document Type: Article Affiliation country: 07391102.2020.1776639