Insight into the structural requirement of aryl sulphonamide based gelatinases (MMP-2 and MMP-9) inhibitors – Part I: 2D-QSAR, 3D-QSAR topomer CoMFA and Naïve Bayes studies – First report of 3D-QSAR Topomer CoMFA analysis for MMP-9 inhibitors and jointly inhibitors of gelatinases together

ABSTRACT

Gelatinases [gelatinase A – matrix metalloproteinase-2 (MMP-2), gelatinase B – matrix metalloproteinase-9 (MMP-9)] play key roles in many disease conditions including cancer. Despite some research work on gelatinases inhibitors both jointly and individually had been reported, challenges still exist in achieving potency as well as selectivity. Here in part I of a series of work, we have reported the structural requirement of some arylsulfonamides. In particular, regression-based 2D-QSARs, topomer CoMFA (comparative molecular field analysis) and Bayesian classification models were constructed to refine structural features for attaining better gelatinase inhibitory activity. The 2D-QSAR models exhibited good statistical significance. The descriptors nsssN, SHBint6, SHBint7, PubchemFP629 were directly correlated with the MMP-2 binding affinities whereas nsssN, SHBint10 and AATS2i were directly proportional to MMP-9 binding affinities. The topomer CoMFA results indicated that the steric and electrostatic fields play key roles in gelatinase inhibition. The established Naïve Bayes prediction models were evaluated by fivefold cross validation and an external test set. Furthermore, important molecular descriptors related to MMP-2 and MMP-9 binding affinities and some active/inactive fragments were identified. Thus, these observations may be helpful for further work of aryl sulphonamide based gelatinase inhibitors in future.

KEYWORDS:

• Gelatinase
• cancer
• QSAR
• S-MLR
• ANN
• SVM
• topomer CoMFA
• Naïve Bayes
• fingerprint

Acknowledgements

Sanjib Das is thankful to AICTE, New Delhi, India for awarding National Doctoral Fellowship (NDF). Sk. Abdul Amin sincerely acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi, India for awarding a Senior Research Fellowship (SRF) [file no. 09/096(0967)/2019-EMR-I, dated: 01-04-2019]. Tarun Jha is thankful for the financial support from RUSA 2.0 of UGC, New Delhi, India to Jadavpur University, Kolkata, India. We thankfully acknowledge Dr Shovanlal Gayen of Jadavpur University, Kolkata, India for his critical discussion. 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.2021.1955414.