Exploring in house glutamate inhibitors of matrix metalloproteinase-2 through validated robust chemico-biological quantitative approaches

• Published in: Structural chemistry 2018-02, Vol.29 (1), p.285-297
• Main Authors: Adhikari, Nilanjan, Amin, Sk. Abdul, Saha, Achintya, Jha, Tarun
• Format: Article
• Language: English
• Subjects: Aliphatic compounds; Aromatic compounds; Cancer; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Homology; In house; Inhibitors; Molecular docking; Original Research; Physical Chemistry; Selectivity; Theoretical and Computational Chemistry
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-017-1028-6

Matrix metalloproteinase-2 (MMP-2) is established as one of the most important metalloenzymes for targeting cancer. However, homologous MMP-9 of the gelatinase family is implicated as an antitarget of cancer. Therefore, it is an important and challenging task to achieve MMP-2 selectivity over MMP-9. In this article, robust validated chemico-biological quantitative approaches were conducted on a series of in house glutamate-based selective MMP-2 inhibitors over MMP-9 for further refinement of our MMP-2 inhibitor designing approach. The two-dimensional quantitative structure-activity relationship (2D-QSAR) study suggested that arylsulfonamide moiety was better than arylcarboxamide function, which in turn, supported by the hologram QSAR (HQSAR), 3D-QSAR comparative molecular field analysis (CoMFA), and comparative molecular similarity analysis (CoMSIA) studies. Regarding the MMP-2 selectivity, glutamines were better than isoglutamines as evidenced by the quantitative activity-activity relationship (QAAR) and molecular docking studies. Favorable hydrophobic and steric features of aryl function directed towards the S1′ pocket were also well attributed. Naphthyl and p -bromophenoxyphenyl moieties in place of biphenyl function were found to be unfavorable for MMP-2 inhibition and selectivity over MMP-9. Linear or cyclic aliphatic group directed towards the S2′ pocket was favorable, whereas branching was unfavorable for MMP-2 inhibition and selectivity. The importance of biphenyl and 3,5-bistrifluoromethylbenzyl functions directed towards the S1′ and S2′ pockets, respectively, was well attributed for potent MMP-2 inhibition and selectivity over MMP-9.