A robust classification-dependent multi-molecular modelling study on some biphenyl sulphonamide based MMP-8 inhibitors

ABSTRACT

Matrix metalloproteinases (MMPs) are a group of zinc and calcium-dependent endopeptidases, which contribute to different physiological and biological activities via extracellular matrix (ECM) degradation. Matrix metalloproteinase-8 (MMP-8) belongs to type-II collagenases of the MMP family that has contribution in several physiological disorders such as cardiovascular diseases, joint, renal, digestive and respiratory disorders as well as in cancer. In clinical study, MMP-8 is found to be associated with periodontal disease condition. Therefore, MMP-8 specific inhibitors should be developed to target these disorders. The biphenyl sulphonamide (BPS) moiety is one of the crucial structural characteristics found in several MMP-8 inhibitors. Here, different classification-based molecular modelling methods were used to explore the structural features that lead to the activity variation of a series of MMP-8 inhibitors possessing a BPS moiety. Our current classification-based structural analysis of these BPS-derived MMP-8 inhibitors was able to identify the importance of several structural features such as the tetrahydroisoquinoline and N-Boc pyridyl groups, which have positive influences on MMP-8 inhibition. This study was also reflected the importance of the zinc-binding groups (ZBGs) like the hydroxamate and phosphonate for potent and sub-nanomolar range MMP-8 inhibition, which may benefit the development of highly potent MMP-8 inhibitors.

KEYWORDS:

• MMP-8 inhibitor
• classification-based QSAR
• LDA
• Bayesian classification
• recursive partitioning
• SARpy

Acknowledgements

SG is grateful to the All India Council for Technical Education (AICTE), New Delhi for awarding scholarship. SKB is thankful to Indian Council of Medical Research (ICMR), New Delhi, India, for awarding the senior research fellowship (SRF) [FILE NO.: 45/29/2019-PHA, dated: 21-06-2019]. SB is thankful to the Swami Vivekananda Merit-cum-Means (SVMCM) scholarship, Govt. of West Bengal, India, for awarding fellowship. TJ is thankful for the financial support from RUSA 2.0 of UGC, New Delhi, India, to Jadavpur University, Kolkata, India. We are very much thankful to the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, for providing the research facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1976831.

Additional information

Funding

This work was supported by the All India Council for Technical Education; Indian Council of Medical Research (ICMR), Govt. of India [45/29/2019-PHA].