Molecular insights in repurposing selective COX-2 inhibitor celecoxib against matrix metalloproteinases in potentiating delayed wound healing: a molecular docking and MMPB/SA based analysis of molecular dynamic simulations

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a role in healing, including reducing inflammation, promoting fibroblast and keratinocyte migration, and modifying scar tissue. Due to their pleiotropic functions in the wound-healing process in diabetic wounds, MMPs constitute a significant cause of delayed wound closure. COX-2 inhibitors are proven to inhibit inflammation. The present study aims to repurpose celecoxib against MMP-2, MMP-8 and MMP-9 through in silico approaches, such as molecular docking, molecular dynamics, and MMPB/SA analysis. We considered five selective COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib, rofecoxib and valdecoxib) for our study against MMPs. Based on molecular docking study and hydrogen bonding pattern, celecoxib in complex with three MMPs was further analyzed using 1 µs (1000 ns) molecular dynamics simulation and MMPB/SA techniques. These studies identified that celecoxib exhibited significant binding affinity −8.8, −7.9 and −8.3 kcal/mol, respectively, against MMP-2, MMP-8 and MMP-9. Celecoxib formed hydrogen bonding and hydrophobic (π–π) interactions with crucial substrate pocket amino acids, which may be accountable for their inhibitory nature. The MMPB/SA studies showed that electrostatic and van der Waal energy terms favoured the total free binding energy component, while polar solvation terms were highly disfavored. The in silico analysis of the secondary structures showed that the celecoxib binding conformation maintains relatively stable along the simulation trajectories. These findings provide some key clues regarding the accommodation of celecoxib in the substrate binding S1’ pocket and also provide structural insights and challenges in repurposing drugs as new MMP inhibitors with anti-inflammatory and anti-inflammatory wound-healing properties.

Communicated by Ramaswamy H. Sarma

Keywords:

• COX-2 inhibitors
• celecoxib
• MMPs
• molecular docking
• MMPB/SA
• molecular dynamics

Acknowledgement

The authors would like to thank the Department of Science and Technology – Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi, for their infrastructure support to our department.

Disclosure statement

The authors declare that there are no conflicts of interest in this study. The authors alone are responsible for the content and writing of the paper.

Data availability statement

Data sharing is not applicable - no new data is generated, or the article describes entirely theoretical research.

Additional information

Funding

Miss Lavanya M would like to thank the All India Council of Technical Education-National Doctoral Fellowship (AICTE-NDF), Government of India, New Delhi, for funding through the project NDF-SRF (App. No. 62302).