Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M pro and Papain-like Protease PL pro of SARS-CoV-2.

التفاصيل البيبلوغرافية
العنوان:	Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M ^pro and Papain-like Protease PL ^pro of SARS-CoV-2.
المؤلفون:	Santos LH; Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil., Kronenberger T; Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, DE72076 Tübingen, Germany.; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery (TüCAD2), Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany., Almeida RG; Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil., Silva EB; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., Rocha REO; Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil., Oliveira JC; Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil., Barreto LV; Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil., Skinner D; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., Fajtová P; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States.; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague, Czech Republic., Giardini MA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., Woodworth B; Department of Medicine, Division of Infectious Diseases, University of California San Diego, La Jolla, California 92093, United States., Bardine C; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, United States., Lourenço AL; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, United States., Craik CS; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, United States., Poso A; Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, DE72076 Tübingen, Germany.; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland., Podust LM; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., McKerrow JH; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., Siqueira-Neto JL; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., O'Donoghue AJ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0657, United States., da Silva Júnior EN; Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil., Ferreira RS; Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
المصدر:	Journal of chemical information and modeling [J Chem Inf Model] 2022 Dec 26; Vol. 62 (24), pp. 6553-6573. Date of Electronic Publication: 2022 Aug 12.
نوع المنشور:	Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة:	English
بيانات الدورية:	Publisher: American Chemical Society Country of Publication: United States NLM ID: 101230060 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-960X (Electronic) Linking ISSN: 15499596 NLM ISO Abbreviation: J Chem Inf Model Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: Washington, D.C. : American Chemical Society, c2005-
مواضيع طبية MeSH:	Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/antagonists & inhibitors, Humans ; COVID-19 ; Molecular Docking Simulation ; Papain
مستخلص:	The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (M ^pro ) and papain-like protease (PL ^pro ) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against M ^pro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against M ^pro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PL ^pro . Four compounds inhibited M ^pro with half-maximal inhibitory concentration (IC 50 ) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PL ^pro with IC 50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of M ^pro and PL ^pro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific M ^pro and PL ^pro inhibitors. Molecular dynamics simulations suggest stable binding modes for M ^pro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PL ^pro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.
التعليقات:	Update of: bioRxiv. 2022 Jan 05;:. (PMID: 35018373)
معلومات مُعتمدة:	U19 AI171110 United States AI NIAID NIH HHS
المشرفين على المادة:	0 (Antiviral Agents) 0 (Naphthoquinones) EC 3.4.22.2 (Papain) 0 (Protease Inhibitors) EC 3.4.22.- (3C-like proteinase, SARS-CoV-2) EC 3.4.22.28 (Coronavirus 3C Proteases) EC 3.4.22.2 (papain-like protease, SARS-CoV-2) EC 3.4.22.2 (Coronavirus Papain-Like Proteases)
تواريخ الأحداث:	Date Created: 20220812 Date Completed: 20230104 Latest Revision: 20240210
رمز التحديث:	20240210
DOI:	10.1021/acs.jcim.2c00693
PMID:	35960688
قاعدة البيانات:	MEDLINE

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الوصف
تدمد:	1549-960X
DOI:	10.1021/acs.jcim.2c00693