Journal Article Ppublish
PubMed: 42647061 DOI: 10.1002/cmdc.70448
Investigating the Binding Mode of a Naphthol-Based Inhibitor Targeting SARS-CoV-2 Main Protease.
ChemMedChem 21(16):e70448
Authors: Ifigeneia Akrani, Haifa El Kilani, Franck Touret, Sophia Kouvali, Veronika Gourni, Aggeliki Tsoka, Joulia K Tsetis, Constantinos Vorgias, Rolf Hilgenfeld, Ioannis K Kostakis, Vassilios Myrianthopoulos, Emmanuel Mikros
Affiliations
- Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
- Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.
- Unité des Virus Émergents (UVE: Aix-Marseille Univ, Università di Corsica, Institution IRD 190, Inserm 1207, RBA), Marseille, France.
- Department of Biology, National and Kapodistrian University of Athens, Athens, Greece.
- Uni-Pharma S.A. Athens, Greece.
- Pharma-Informatics Unit, Athena Research and Innovation Center in Information Communication and Knowledge Technologies, Marousi, Greece.
Abstract
Regardless of the massive global efforts to combat the virus causing SARS-CoV-2 syndrome, the infection remains a substantial health challenge worldwide in the years following 2019. To this direction, targeting the main viral protease M pro has been proposed as a tractable and particularly promising approach toward developing effective and safe COVID-19 antivirals. By applying an integrated workflow combining a previously developed in silico consensus ranking protocol with two orthogonal in vitro methods, the NCI/DTP repository is screened and the discovery of an original naphthol scaffold with M pro inhibitory properties is reported. The hit is characterized in terms of structure and binding thermodynamics by combining X-ray crystallography and isothermal titration calorimetry where a binding affinity constant of 1.55 μM is determined. The compound is further evaluated against virus-infected cells, where an EC 50 value of 7.23 μM and comparable toxicity with nirmatrelvir are measured. Chemical synthesis is additionally employed to facilitate optimal exploration of the structure-activity relationship landscape regarding the new hit. By integrating computational, biophysical, and enzymatic methods, the suggested approach allows the combination of a structural hypothesis with functional evidence and shows its capacity toward identifying and rationally optimizing structurally original noncovalent M pro inhibitors.
MeSH
Sars-Cov-2, Biophysics, Chemistry, Pharmaceutical, Naphthols, Viruses, Peptide Hydrolases, Severe Acute Respiratory Syndrome-Related Coronavirus, Antiviral Agents