A Cross-Docking Study on Matrix Metalloproteinase Family

Area of Science:

• Biochemistry and Structural Biology
• Computational Chemistry
• Drug Discovery

Background:

• Matrix metalloproteinases (MMPs) are key enzymes in physiological and pathological processes, including cancer and cardiovascular diseases.
• Dysregulation of MMP activity is linked to various diseases, necessitating effective therapeutic strategies.
• The availability of numerous 3D structures for MMPs presents a challenge in selecting appropriate targets for virtual screening.

Purpose of the Study:

• To evaluate and rank available matrix metalloproteinase (MMP) structures for their suitability in virtual screening protocols.
• To identify specific MMP structures that yield the best performance in virtual screening based on cross-docking metrics.
• To guide the selection of optimal protein targets for developing novel MMP inhibitors.

Main Methods:

• Employed a cross-docking approach to assess the performance of 123 holo structures across seven MMP enzyme groups (MMP-1, -3, -7, -8, -9, -12, -13).
• Calculated the average root mean square deviation (RMSD) to rank the suitability of different MMP structures for virtual screening.
• Analyzed the impact of structural flexibility, resolution, binding affinity, ligand size, and chemotype on cross-docking outcomes.

Main Results:

• MMP structures with higher residue flexibility showed poorer performance (fewer structures with RMSD < 2.0 Å).
• Cross-docking results and average RMSD were significantly influenced by factors such as protein resolution, binding affinity, ligand size, and co-crystalized ligand chemotype.
• The top-ranked MMP-12 receptors, identified by average RMSD, demonstrated high enrichment factors (EF1%) in retrospective screening.

Conclusions:

• Structures with lower average RMSD are highly probable candidates for successful virtual screening of MMP inhibitors.
• This study provides a validated methodology for receptor selection in MMP virtual screening, enhancing the efficiency of inhibitor discovery.
• The findings facilitate improved enrichment of potent MMP inhibitors through strategic selection of screening targets.