3D QSAR pharmacophore-based virtual screening and molecular docking studies to identify novel matrix metalloproteinase 12 inhibitors

摘要

Matrix metalloproteinase 12 (MMP-12) is a potential therapeutic target for the treatment of chronic obstructive pulmonary disorder and other inflammatory disorders. Ligand-based 3D QSAR pharmacophore modelling approach was employed to reveal structural and chemical features necessary for the inhibition of MMP-12. The best HypoGen pharmacophore model Hypo1 for MMP-12 inhibitors contains two hydrogen bond acceptors, one hydrophobic aliphatic and one hydrophobic aromatic feature. Molecular docking studies of all inhibitors showed hydrogen bond interactions with important amino acids (Glu219, Ala182 and Leu181), and these interactions were compared with Hypo1, which shows that the Hypo1 has a good predictive ability. The best pharmacophore hypothesis was further cross-validated using test set, decoy set and Cat-Scramble methodology. The validated pharmacophore model Hypo1 was used for screening the chemical databases of small compounds, including Specs, NCI and ChemDiv, to identify the new compounds that are presumably able to act as MMP-12 inhibitors. The screened virtual hits from Hypo1 were subjected to several filters such as toxicity, quantitative estimation of drug-likeness and molecular docking analysis. Finally, four novel compounds with diverse scaffolds were selected as possible candidates for the designing of potent MMP-12 inhibitors.