Mohammad Ramezani, Jamal Shamsara1. 1. Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. shamsaraj@mums.ac.ir.
Abstract
BACKGROUND: Matrix metalloproteinases (MMPs) contribute to various physiological and pathophysiological processes. An imbalance in MMP activity causes pathological conditions including inflammatory diseases, cancer, and cardiovascular diseases. Each MMP member has many 3D structures available; therefore, selecting one structure for virtual screening becomes challenging. METHODS: In this study, we used the cross-docking approach to rank the available MMP structures for their probable successful performance in virtual screening. To determine structures that would offer best average RMSD (root mean square deviation), we performed cross-docking studies on 123 holo (protein-ligand) structures of seven MMP enzyme groups (MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13). RESULTS: MMP enzymes with more flexible residues had fewer structures with RMSD < 2.0 A. Further, same resolution and binding affinities, difference in ligand size, and chemotype of the co-crystalized ligand were parameters that could greatly affect the corresponding cross-dock results and the calculated average RMSD for the structures. Four of the six best MMP-12 receptors, which were identified using the average RMSD metric, had the highest EF1% (emrichment factor) in the retrospective enrichment study. CONCLUSION: According to the enrichment results, structures with lower average RMSD have a high probability of being appropriate candidates. These study findings will help in receptor selection for an MMP virtual screening protocol and lead to better enrichment of MMP inhibitors.
BACKGROUND: Matrix metalloproteinases (MMPs) contribute to various physiological and pathophysiological processes. An imbalance in MMP activity causes pathological conditions including inflammatory diseases, cancer, and cardiovascular diseases. Each MMP member has many 3D structures available; therefore, selecting one structure for virtual screening becomes challenging. METHODS: In this study, we used the cross-docking approach to rank the available MMP structures for their probable successful performance in virtual screening. To determine structures that would offer best average RMSD (root mean square deviation), we performed cross-docking studies on 123 holo (protein-ligand) structures of seven MMP enzyme groups (MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MMP-13). RESULTS:MMP enzymes with more flexible residues had fewer structures with RMSD < 2.0 A. Further, same resolution and binding affinities, difference in ligand size, and chemotype of the co-crystalized ligand were parameters that could greatly affect the corresponding cross-dock results and the calculated average RMSD for the structures. Four of the six best MMP-12 receptors, which were identified using the average RMSD metric, had the highest EF1% (emrichment factor) in the retrospective enrichment study. CONCLUSION: According to the enrichment results, structures with lower average RMSD have a high probability of being appropriate candidates. These study findings will help in receptor selection for an MMP virtual screening protocol and lead to better enrichment of MMP inhibitors.