Homology modeling and inhibitors of hSGLTs

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Abstract

The sodium-dependent glucose co-transporters (SGLTs) are membrane proteins that function by harnessing the energy stored in transmembrane sodium gradients to actively transport sugars, which are crucial for maintaining cellular energy homeostasis. In humans, dietary glucose is imported via SGLT1 (hSGLT1) in the small intestines, while hSGLT2 reabsorbs filtered glucose in the kidneys. Diabetic patients suffer from improper sugar handling that results in dangerously high levels of plasma glucose, and it has been proposed that reduction of blood glucose levels in type 2 diabetics could be achieved through inhibiting SGLTs. Unfortunately, hSGLT1 inhibition leads to severe diarrhea and dehydration due to osmotic imbalance in the intestines. However, inhibition of hSGLT2 has minimal side effects making it a promising drug target. The recent crystal structure of the bacterial homolog of hSGLTs, vSGLT, has made it possible to rationally pursue drug discovery efforts. At the center of our investigation is the identification of high affinity ligands for vSGLT, hSGLT1, and hSGLT2 using computational methods. The ultimate goal is to identify specific inhibitors to hSGLT2 that have low affinity for hSGLT1. We created homology models of hSGLT1 and hSGLT2 based on the vSGLT structure and then carried out structure-based in silico inhibitor screens against all three transporters. Over 9.5 million compounds were screened from 7 libraries in the Zinc database, and we present the top candidates for each membrane protein along with their predicted poses. Since our ultimate goal is to target hSGLT2 and not hSGLT1, we focus on those compounds with maximal differentiation. Additionally, we report high affinity hits against vSGLT, which have the potential to aid in crystallizing the transporter in new conformations. We successfully modeled hSGLT1 and hSGLT2, and our model structures closely resemble the overall fold of the template structure vSGLT. Many of the top ligands possess 2 main chemical features of known hSGLT2 inhibitors: a six-membered ring that superposes with the galactose in the sugar-binding site and a long tail that contain phenyl rings. These new ligands have the potential to generate new pharmacophores.