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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Translational Pharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1390705
This article is part of the Research Topic Pharmacoinformatics: New developments and challenges in drug design View all 10 articles
Repurposing the Open Global Health Library for the disCoVery of novel Mpro destabilizers with scope as broad-spectrum antivirals
Provisionally accepted
FRANCISCO CASTILLO
1*
David Ramirez
2*
Maria C. Ramos
1
Blanca Martinez-Arribas
3
Elisabeth Domingo-Contreras
1
Thomas A. Mackenzie
1
Carlos A. Peña-Varas
2
Sven Lindemann
4
Fernando Montero
5
Frederick Annang
1
FRANCISCA VICENTE
1
Olga Genilloud
1
Dolores González-Pacanowska
3
Rosario Fernandez
1- 1 Fundación MEDINA, Granada, Spain
- 2 Departamento de Farmacología, Facultad de Ciencias Biológicas. Universidad de Concepción, 4030000 Concepción, Chile, santiago chile, Chile
- 3 Institute of Parasitology and Biomedicine López-Neyra, Spanish National Research Council (CSIC), Granada, Spain
- 4 Merck (Germany), Darmstadt, Hesse, Germany
- 5 Departamento Química-Física. Facultad de Ciencias. Universidad de Granada, Granada, Spain
The emergence of new variants of concern (VoC) of coronaviruses, potentially more vaccineresistant and less sensitive to existing treatments, is evident based on the high prevalence. A prospective spread of such VoCs demands a preparedness that can be met by fast-tracking workflows aiming at viral proteins target with a clear in vitro/in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and in the production and function of viral polyproteins. These roles are conserved amongst betacoronaviruses like HcoV-OC43 and SARS-CoV-2, which makes the identification of new inhibitors for them a good starting point to designing broad-spectrum antivirals. We report an optimized methodology based on orthogonal cell-free assays to identify small-molecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HcoV-OC43-Mpro, which blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of a new antiviral activity for compound OGHL98. In silico molecular dynamics dissecting intermolecular interactions between OGHL98 and both proteases concluded that the binding mode was primary ruled by conserved H-bonds with their C-terminal amino acids and that the rational design on OGHL98 has scope against VoC proteases.
Keywords: COVID-19, Betacoronavirus, HTS M-PRO Thermal shift, molecular dynamics simulations, molecular docking, Antiviral Agents
Received: 23 Feb 2024; Accepted: 29 May 2024.
Copyright: © 2024 CASTILLO, Ramirez, Ramos, Martinez-Arribas, Domingo-Contreras, Mackenzie, Peña-Varas, Lindemann, Montero, Annang, VICENTE, Genilloud, González-Pacanowska and Fernandez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
FRANCISCO CASTILLO, Fundación MEDINA, Granada, Spain
David Ramirez, Departamento de Farmacología, Facultad de Ciencias Biológicas. Universidad de Concepción, 4030000 Concepción, Chile, santiago chile, Chile
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