Virtual High-Throughput Screening for Matrix Metalloproteinase Inhibitors

Abstract

Structure-based virtual screening (SBVS) is a common method for the fast identification of hit structures at the beginning of a medicinal chemistry program in drug discovery. The SBVS, described in this manuscript, is focused on finding small molecule hits that can be further utilized as a starting point for the development of inhibitors of matrix metalloproteinase 13 (MMP-13) via structure-based molecular design. We intended to identify a set of structurally diverse hits, which occupy all subsites (S1'-S3', S2, and S3) centering the zinc containing binding site of MMP-13, by the virtual screening of a chemical library comprising more than ten million commercially available compounds. In total, 23 compounds were found as potential MMP-13 inhibitors using Glide docking followed by the analysis of the structural interaction fingerprints (SIFt) of the docked structures.

Keywords: Docking; Matrix metalloproteinase; Structural interaction fingerprints; Structure-based virtual screening; Zn-chelating inhibitor.

Figure 1

Broad-spectrum MMP inhibitors.

Figure 2

Non-zinc chelating MMP-13 inhibitors

Figure 3

Virtual screening process and outcomes

Figure 4

Superimposed X-ray co-crystal structures of MMP isozymes (A) and Zn-chelating inhibitors (B). Substrate mimetic (decapeptide) is represented as a surface (PDB ID: 3AYU) (A). Each subsite in the substrate-binding cleft is annotated (A) [29].

Figure 5

Structural interaction fingerprints and binding poses of ligands clustered based on their interactions with the target structure. Blue circle represents the Zn-binding site. The color code in the map represents the average of the Glide docking score of different ligands clustered in each cell. It ranges from -6.6 (white, highest score) to -1.8 (dark, lowest score). The top left cell (A) of the map represents ligands occupying the S2 site, the top middle cell (B) represents ligands interacting with the S1’ site, the top right cell (C) represents ligands occupying the S2’ and S3’ sits, the bottom left cell (D) represent ligands binding the area between the subsites S2 and S3, and the middle bottom cell (E) represents the ligands occupying the S3 site.

Figure 6

Representative hits and their binding poses in MMP-13. (A) ZINC62430943, (B) ZINC82305218, (C) ZINC41498653, and (D) ZINC57989822 are shown in green sticks. Amino acids in the active site of MMP-13 are shown in gray sticks, and protein structures are shown in a gray ribbon diagram. Figures were generated using the program PyMol.[31]