Lead identification and optimization of novel collagenase inhibitors; pharmacophore and structure based studies

Abstract

In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors have been developed with the aid of HypoGen module within Catalyst program package. In MMP-1 and MMP-13, all the compounds in the training set mapped HBA and RA, while in MMP-8, the training set mapped HBA and HY. These features revealed responsibility for the high molecular bioactivity, and this is further used as a three dimensional query to screen the knowledge based designed molecules. These pharmacophore models for collagenases picked up some potent and novel inhibitors. Subsequently, docking studies were performed for the potent molecules and novel hits were suggested for further studies based on the docking score and active site interactions in MMP-1, MMP-8 and MMP-13.

Keywords: Collagenases; HypoGen; Induced Fit; Osteoarthritis; Pharmacophore; S1' loop.

Figure 1

Structures of some of the training set molecules for (a) MMP-1, (b) MMP-8 & (c) MMP-13 (experimental IC50 values, in parentheses).

Figure 2

Hypogen feature with its distance constraints, features are color coded with green: hydrogen bond acceptor, magenta: hydrogen bond donor, white: ring aromatic and blue: hydrophobic for MMP-1, MMP-8 and MMP-13.

Figure 3

Shows Hypo-1, 11&21 mapping to highly active and low active compounds for MMP-1, MMP-8 & MMP-13

Figure 4

Some of the newly identified potent lead molecules for (a) MMP-1, (b) MMP-8 & (c) MMP-13.

Figure 5

Shows docked conformations of molecule 66, 69 & 72 in the S1 loop of MMP-1, MMP-8 & MMP-13 respectively. Dotted lines represent hydrogen bonds. Hydrophobic interactions are represented as arcs. Ligand represented as ball and sticks.