Understanding Chemico‐Biological Interactions of Glutamate MMP‐2 Inhibitors through Rigorous Alignment‐Dependent 3D‐QSAR Analyses

• Published in: ChemistrySelect (Weinheim) 2017-09, Vol.2 (26), p.7888-7898
• Main Authors: Adhikari, Nilanjan, Amin, Sk Abdul, Saha, Achintya, Jha, Tarun
• Format: Article
• Language: English
• Subjects: Alignment-dependent 3D-QSAR; Glutamate-based MMP-2 inhibitor; Molecular docking study; Open3DALIGN; Pharmacophore mapping
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.201701330

The current study involves different alignment techniques (pharmacophore‐based, docking‐based and Open3DALIGN‐based) extensively at the first time to build three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models on some potential glutamate‐based in house MMP‐2 inhibitors. The docking‐based alignment method yields the best 3D‐QSAR models though other alignment‐based methods also provide statistically significant and validated models. 3D‐QSAR models are correlated with molecular docking study and pharmacophore mapping. Biphenyl moiety of glutamines enters into the S1′ pocket and involves π‐π interactions with Tyr142 and His120, while none of the phenylacetyl/naphthylacetyl isoglutamines interacts with Tyr142. 3D‐QSAR models also suggest the importance of hydrophobicity and steric features of biphenyl function required for higher MMP‐2 inhibition. The sulfonyl oxygen may form potential hydrogen bonding interaction with Leu83 and Ala84 of S1' pocket. This study clearly points out that biphenylsulfonyl glutamines are favorable than phenylacetyl/naphthylacetyl isoglutamines for imparting higher MMP‐2 inhibition. Different alignment techniques are used to construct multiple 3D‐QSAR models in order to check which type of alignment will produce the best model. The docking‐based alignment method results in the best model that is validated by pharmacophore mapping study. Ring aromaticity, stric and hydrophobic feature of biphenyl moiety is crucial for higher MMP‐2 inhibition. Glutamines are better MMP‐2 inhibitors than isoglutamines.