Supplementary file 1_Discovery of potent and highly selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for treating diabetic nephropathy.docx

Inhibition of glucose reabsorption by SGLT2 in the kidney is a promising strategy for the treatment of diabetic nephropathy. Adverse side effects of SGLT1 inhibition can be reduced by selective inhibition of SGLT2. Here, we developed an integrated virtual screening approach (combining drug-likeness analysis, pharmacophore model recognition, molecular docking experiments, and interaction analysis) to discover novel SGLT2 inhibitors. In vitro experiments suggested that all of the hits had strong inhibitory effects against SGLT2 with IC50 values ranging from 1.5 nM to 196 nM. Particularly, hit 4 showed an excellent inhibition of SGLT2 (IC50 = 1.5 ± 0.3 nM) and high SGLT1/SGLT2 selectivity of 3510-fold. Furthermore, in vivo treatment experiments showed it could enhance the renal glucose excretion, reduce the blood glucose and ameliorate renal function in the diabetic mice. Our results indicate that hit 4 is expected to become a promising drug candidate for treating diabetic nephropathy.