Discovery of dual-target natural inhibitors of meprins α and β metalloproteases for inflammation regulation: pharmacophore modelling, molecular docking, ADME prediction, and molecular dynamics studies

ABSTRACT

Meprins, zinc-dependent metalloproteinases belonging to the metzincin family, have been associated with various inflammatory diseases due to their abnormal expression and activity. In this study, we utilized pharmacophore modelling to identify crucial features for discovering potential dual inhibitors targeting meprins α and β. We screened four pharmacophoric features against a library of 270,540 natural compounds from the Zinc database, resulting in 84,092 matching compounds. Molecular docking was then performed on these compounds, targeting the active sites of meprins α and β. Docking results revealed six compounds capable of interacting with both isoforms, with binding affinities ranging from −10.0 to −10.5 kcal/mol and −6.9 to −9.9 kcal/mol for meprin α and β, respectively. Among these compounds, ZINC000008790788 and ZINC000095099469 displayed superior docking scores and MM-GBSA binding free energy compared to reference ligands. Furthermore, these two compounds exhibited acceptable predicted pharmacokinetic properties and stable interactions with meprins α and β during molecular dynamics simulations. This study presents a comprehensive approach for identifying potential dual inhibitors of meprin α and β, offering insights into the development of therapeutic interventions for inflammatory diseases associated with meprin dysregulation.

KEYWORDS:

• Inflammation
• meprins α and β
• dual targeting
• E-pharmacophore
• docking
• molecular dynamics

Acknowledgments

The authors gratefully acknowledged the approval and the support of this research study by the grant no. NBU-FFR-2023-0145451014550 from the Deanship of Scientific Research at Northern Border University Arar. KSA. We acknowledge Mme Katia Dekimeche from Schrodinger for the technical support and help.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary data

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2023.2277425

Additional information

Funding

This project was funded by the Deanship of Scientific Research at Northern Border University Arar. KSA through the project number [NBU-FFR-2023-0145451014550].