Quest for selective MMP9 inhibitors: a computational approach.

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Computational Drug Discovery

Background:

• Matrix Metalloproteinases-9 (MMP-9) is implicated in various diseases, including cancer, Alzheimer's, and arthritis.
• Selective inhibition of MMP-9 is challenging; targeting the zymogen form (pro-MMP-9) offers a novel therapeutic strategy.
• The compound JNJ0966 demonstrated selective inhibition of pro-MMP-9 activation, but no other small molecules have since been identified.

Purpose of the Study:

• To identify novel small molecule inhibitors targeting pro-MMP-9 activation using computational methods.
• To explore potential drug candidates from the ChEMBL database through molecular docking and dynamics simulations.
• To assess the therapeutic potential of identified compounds as anticancer agents.

Main Methods:

• Structure-based virtual screening using the MMP-9 protein structure (PDB ID: 5UE4) with an allosteric inhibitor.
• Molecular docking and MMGBSA binding affinity calculations to identify potential hits.
• ADMET analysis and molecular dynamics (MD) simulations to evaluate the properties and stability of top candidates.

Main Results:

• Five potential inhibitor candidates were identified from the ChEMBL database.
• All identified hits demonstrated superior performance compared to JNJ0966 in docking, ADMET analysis, and MD simulations.
• The selected molecules exhibit favorable binding affinity and stability in the allosteric pocket of MMP-9.

Conclusions:

• The identified small molecules represent promising leads for developing novel pro-MMP-9 inhibitors.
• These compounds warrant further investigation through in vitro and in vivo studies for potential anticancer applications.
• The findings may accelerate the development of drugs targeting pro-MMP-9 for various diseases.