Identification of 13 Guanidinobenzoyl- or Aminidinobenzoyl-Containing Drugs to Potentially Inhibit TMPRSS2 for COVID-19 Treatment.

Antiviral Agents / chemistry Benzamidines / chemistry Binding Sites COVID-19 / pathology Catalytic Domain Esters / chemistry Guanidines / chemistry Humans Molecular Docking Simulation Molecular Dynamics Simulation Serine Endopeptidases / chemistry Serine Proteinase Inhibitors / chemistry Thermodynamics COVID-19 Drug Treatment
COVID-19 SARS-CoV-2 TMPRSS2 docking drug molecular dynamics

Journal

International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791

Informations de publication

Date de publication:
30 Jun 2021
Historique:
received: 25 05 2021
revised: 18 06 2021
accepted: 28 06 2021
entrez: 2 7 2021
pubmed: 3 7 2021
medline: 9 7 2021
Statut: epublish

Résumé

Positively charged groups that mimic arginine or lysine in a natural substrate of trypsin are necessary for drugs to inhibit the trypsin-like serine protease TMPRSS2 that is involved in the viral entry and spread of coronaviruses, including SARS-CoV-2. Based on this assumption, we identified a set of 13 approved or clinically investigational drugs with positively charged guanidinobenzoyl and/or aminidinobenzoyl groups, including the experimentally verified TMPRSS2 inhibitors Camostat and Nafamostat. Molecular docking using the C-I-TASSER-predicted TMPRSS2 catalytic domain model suggested that the guanidinobenzoyl or aminidinobenzoyl group in all the drugs could form putative salt bridge interactions with the side-chain carboxyl group of Asp435 located in the S1 pocket of TMPRSS2. Molecular dynamics simulations further revealed the high stability of the putative salt bridge interactions over long-time (100 ns) simulations. The molecular mechanics/generalized Born surface area-binding free energy assessment and per-residue energy decomposition analysis also supported the strong binding interactions between TMPRSS2 and the proposed drugs. These results suggest that the proposed compounds, in addition to Camostat and Nafamostat, could be effective TMPRSS2 inhibitors for COVID-19 treatment by occupying the S1 pocket with the hallmark positively charged groups.

Identifiants

DOI: 10.3390/ijms22137060 PMID: 34209110 PMC: PMC8269196
pubmed: 34209110
pii: ijms22137060
doi: 10.3390/ijms22137060
pmc: PMC8269196
pii:
doi:

Substances chimiques

Antiviral Agents 0
Benzamidines 0
Esters 0
Guanidines 0
Serine Proteinase Inhibitors 0
camostat 0FD207WKDU
Serine Endopeptidases EC 3.4.21.-
TMPRSS2 protein, human EC 3.4.21.-
nafamostat Y25LQ0H97D

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NIH HHS
ID : S10OD026825
Pays : United States
Organisme : NIH HHS
ID : S10 OD026825
Pays : United States
Organisme : NIH HHS
ID : GM136422
Pays : United States
Organisme : NIH HHS
ID : U24CA210967
Pays : United States
Organisme : National Science Foundation
ID : IIS1901191
Organisme : National Science Foundation
ID : DBI2030790
Organisme : NIEHS NIH HHS
ID : P30 ES017885
Pays : United States
Organisme : NIH HHS
ID : P30ES017885
Pays : United States
Organisme : NIH HHS
ID : AI134678
Pays : United States

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Auteurs

Xiaoqiang Huang (X)

Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
ORCID: 0000-0002-1005-848X

Robin Pearce (R)

Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.

Gilbert S Omenn (GS)

Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
Departments of Internal Medicine and Human Genetics and School of Public Health, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
ORCID: 0000-0002-8976-6074

Yang Zhang (Y)

Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
Department of Biological Chemistry, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.

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Classifications MeSH

Recherchemedicale.com › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Composés chimiques organiques › Amidines › Benzamidines › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Domaine catalytique › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Composés chimiques organiques › Acides carboxyliques › Esters › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Composés chimiques organiques › Amidines › Guanidines › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de docking moléculaire › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Protéases à sérine › Serine endopeptidases › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéases › Inhibiteurs de la sérine protéinase › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Phénomènes physiques › Thermodynamique › Identification of 13 Guanidinobenzoyl- or...
Recherchemedicale.com › Thérapeutique › Traitement médicamenteux › Traitements médicamenteux de la COVID-19 › Identification of 13 Guanidinobenzoyl- or...