Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation

Author:

Peralta-Moreno Maria Nuria1ORCID,Mena Yago1,Ortega-Alarcon David23ORCID,Jimenez-Alesanco Ana23ORCID,Vega Sonia2,Abian Olga2345ORCID,Velazquez-Campoy Adrian2345ORCID,Thomson Timothy M.567ORCID,Pinto Marta8,Granadino-Roldán José M.9ORCID,Santos Tomas Maria10,Perez Juan J.11ORCID,Rubio-Martinez Jaime1ORCID

Affiliation:

1. Department of Materials Science and Physical Chemistry, Institut de Recerca en Quimica Teòrica i Computacional (IQTCUB), University of Barcelona (UB), 08028 Barcelona, Spain

2. Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain

3. Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain

4. Instituto de Investigación Sanitaria de Aragón (IIS Aragon), 50009 Zaragoza, Spain

5. Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas Digestivas (CIBERehd), 28029 Madrid, Spain

6. Institute of Molecular Biology of Barcelona (IBMB-CSIC), 08028 Barcelona, Spain

7. Instituto de investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima 15102, Peru

8. AbbVie Deutschland GmbH & Co. KG, Computational Drug Discovery, Knollstrasse, 67061 Ludwigshafen, Germany

9. Departamento de Química Física y Analítica, Facultad de Ciencias Experimentales, Universidad de Jaén, Campus “Las Lagunillas” s/n, 23071 Jaén, Spain

10. Department of Architecture Technology, Universitat Politecnica de Catalunya (UPC), Av. Diagonal 649, 08028 Barcelona, Spain

11. Department of Chemical Engineering, Universitat Politecnica de Catalunya (UPC), Barcelona Tech. Av. Diagonal, 647, 08028 Barcelona, Spain

Abstract

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 μM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.

Funder

The Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR)-Generalitat de Catalunya

Spanish Structures and Excellence María de Maeztu program

Universitat de Barcelona PREDOCS-UB 2020 grant

Fundación hna

Fondo Investiga COVID-19 from Instituto de Investigación Sanitaria de Aragón IIS-A

Spanish Ministry of Economy and Competitiveness

FPI predoctoral contract

Ministry of Science and Innovation

ERDF A way of Making Europe

Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III and European Union

Diputación General de Aragón

Consejo Superior de Investigaciones Científicas

Plataforma Temática Interdisciplinar Salud Global

Agència de Gestió d’Ajuts Universitaris i de Recerca

Plan Nacional de I + D

Publisher

MDPI AG

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