QSAR analysis of sodium glucose co–transporter 2 (SGLT2) inhibitors for anti-hyperglycaemic lead development

ABSTRACT

QSAR (Quantitative Structure Activity Relationship) modelling was performed on a dataset of 90 sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The quantitative and explicative evaluations revealed some of the subtle and distinguished structural features that are responsible for the inhibitory potency of these compounds against SGLT2, such as less possible number of ring carbons at 8 Å from the lipophilic atoms in the molecule (fringClipo8A) and more possible value for the sum of the partial charges of the lipophilic atoms present within seven bonds from the donor atoms (lipo_don_7Bc). Multivariate GA–MLR (genetic algorithm–multi linear regression) and thorough validation methodology out-turned a statistically robust QSAR model with a very high predictability shown from various statistical parameters. A QSAR model with r² = 0.83, F = 51.54, Q²_LOO = 0.79, Q²_LMO = 0.79, CCC_cv = 0.88, Q²Fⁿ = 0.76–0.81, r²_ext = 0.77, CCC_ext = 0.85, and with RMSE_tr < RMSE_cv was proposed. This QSAR model will assist synthetic chemists in the development of the SGLT2 inhibitors as the antidiabetic leads.

KEYWORDS:

• QSAR
• SGLT2
• T2DM
• T1DM
• hyperglycaemia

Acknowledgements

The authors are thankful to Dr. Paola Gramatica and her team for providing QSARINS-v2.2.4 and developers of TINKER, ChemSketch 12 Freeware (ACD labs), and PyDescriptor for providing the free versions of their software. Archana Chapolikar and Ajaykumar Gandhi are thankful to the Government College of Arts and Science, Aurangabad, Maharashtra, India. Magdi E.A. Zaki, Sami A. Al-Hussain, and Anis Ben Ghorbal are thankful to the Deanship of Scientific Research at Imam Mohammad bin Saud Islamic University for funding this work through Research Group no-21-09-77. All the authors are also thankful to Dr. V.T. Dangat (retired former Head, Department of Chemistry, Nowrosjee Wadia College, Pune) and Dr. Talat Khan (assistant professor, department of English, Government College of Arts and Science, Aurangabad, Maharashtra, India for their help in drafting of the manuscript.

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.2021.1971295.

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University for funding this work through RG-21-09-77.