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Updated: Dec 3, 2025
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Molecular docking and molecular dynamics to identify collagenase inhibitors as lead compounds to address
Himadri Shekhar Roy1, Gurudutt Dubey2, Vishnu Kumar Sharma3
1Department of Biological Science, Institute of Nanoscience and Technology (INST), Mohali, Punjab, India.
Abstract:
Osteoarthritis (OA) is a degenerative disease which affects a large number of individuals. Collagenases, which belong to a class of metalloproteases (MMPs), are responsible for the degradation of cartilage manifested in OA. Inhibition of the catalytic domains of these MMPs is one of the important therapeutic strategies proposed for the prevention of OA. The main objective of this work is to evaluate the binding of curcumin and its metabolites with the active sites of collagenases in comparison to standard inhibitors on the basis of our hypothesis that curcumin/metabolites could exhibit an inhibitory effect on MMPs. Here, we report the molecular docking analysis of curcumin and its metabolites with collagenases (MMP-1, MMP-8, MMP-13). Among the molecules tested, curcumin monoglucuronide (CMG) demonstrated the best binding affinity with MMP-13, which is specifically implicated in OA. The CMG-MMP-complexes were further subjected to molecular dynamic simulations to explore the stability of the complexes and to estimate the free binding energies. The results indicated that CMG preferentially bind to MMP-13 in comparison to that of MMP-1 and MMP-8 with binding free energies (ΔGbind) of (-60.55), (-27.02) and (-46.91) kcal/mol, respectively. This is the first study which suggests that curcumin monoglucuronide can be considered as an effective lead compound to prevent the progression of OA.Communicated by Ramaswamy H. Sarma.
Insights
Curcumin monoglucuronide shows potential for osteoarthritis treatment by inhibiting collagenases. This compound effectively binds to MMP-13, a key enzyme in cartilage degradation, suggesting a new therapeutic strategy for OA.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation.
- Matrix metalloproteinases (MMPs), particularly collagenases, play a crucial role in cartilage breakdown in OA.
- Inhibiting MMPs is a therapeutic strategy for OA prevention.
Purpose of the Study:
- To evaluate the binding affinity of curcumin and its metabolites with collagenases (MMP-1, MMP-8, MMP-13).
- To test the hypothesis that curcumin and its metabolites can inhibit MMPs, offering a potential OA treatment.
Main Methods:
- Molecular docking analysis of curcumin and its metabolites against MMP-1, MMP-8, and MMP-13.
- Molecular dynamic simulations to assess the stability and binding free energies of curcumin monoglucuronide (CMG)-MMP complexes.
Main Results:
- Curcumin monoglucuronide (CMG) exhibited the strongest binding affinity with MMP-13, an enzyme implicated in OA.
- CMG demonstrated preferential binding to MMP-13 over MMP-1 and MMP-8, with binding free energies of -60.55, -27.02, and -46.91 kcal/mol, respectively.
- Molecular dynamics simulations confirmed the stability of CMG-MMP complexes.
Conclusions:
- Curcumin monoglucuronide (CMG) is a promising lead compound for preventing osteoarthritis progression.
- CMG's potent inhibition of MMP-13 suggests a novel therapeutic approach for OA.
- This study provides the first evidence for CMG's potential as an effective OA therapeutic agent.
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