Abstract
Matrix metalloproteinases (MMPs) have distinctive roles in various physiological and pathological processes such as inflammatory diseases and cancer. This study explored the performance of eleven scoring functions (D-Score, G-Score, ChemScore, F-Score, PMF-Score, PoseScore, RankScore, DSX, and X-Score and scoring functions of AutoDock4.1 and AutoDockVina). Their performance was judged by calculation of their correlations to experimental binding affinities of 3D ligand-enzyme complexes of MMP family. Furthermore, they were evaluated for their ability in reranking virtual screening study results performed on a member of MMP family (MMP-12). Enrichment factor at different levels and receiver operating characteristics (ROC) curves were used to assess their performance. Finally, we have developed a PCA model from the best functions. Of the scoring functions evaluated, F-Score, DSX, and ChemScore were the best overall performers in prediction of MMPs-inhibitors binding affinities while ChemScore, Autodock, and DSX had the best discriminative power in virtual screening against the MMP-12 target. Consensus scorings did not show statistically significant superiority over the other scorings methods in correlation study while PCA model which consists of ChemScore, Autodock, and DSX improved overall enrichment. Outcome of this study could be useful for the setting up of a suitable scoring protocol, resulting in enrichment of MMPs inhibitors.
Highlights
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a central role in various physiological processes and pathological conditions including cancer and inflammatory diseases
The former has been investigated on a set of 40 MMPs complexes [5]
In our paper we focused on successfully ranking the interaction of different ligands with MMPs
Summary
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a central role in various physiological processes and pathological conditions including cancer and inflammatory diseases. One of the main problems for developing a new class of drugs as MMP inhibitors is the issue of selectivity This family shares a very similar active site that makes traditional chemical approach for developing of selective inhibitors time-consuming. Reliability of molecular docking depends on how the geometry of ligands will be predicted and how the different pose of a ligand and interaction of different ligands with receptor will be ranked [4] The former has been investigated on a set of 40 MMPs complexes [5]. In our paper we focused on successfully ranking the interaction of different ligands with MMPs. Scoring functions are used to estimate the binding affinity of a compound for a receptor in a reasonable time. The first class of scoring functions within this group (force-field based) directly derives the interaction terms from physicochemical
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