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Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Structural selectivity of human SGLT inhibitors.
Charles S Hummel1, Chuan Lu, Jie Liu
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA.
American Journal of Physiology. Cell Physiology
|September 24, 2011
Summary
New diabetes drugs called human sodium-glucose cotransporter (hSGLT) inhibitors block kidney glucose reabsorption. This study reveals how dapagliflozin and related compounds selectively inhibit hSGLT2 over hSGLT1 by examining their binding and dissociation kinetics.
Area of Science:
- Pharmacology
- Biochemistry
- Molecular Biology
Background:
- Human sodium-glucose cotransporter (hSGLT) inhibitors represent a novel class of antidiabetic medications.
- These drugs effectively reduce renal glucose reabsorption, presenting a significant therapeutic avenue for the diabetes epidemic.
- The precise molecular mechanisms underlying their action remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms of human Na(+)-D-glucose cotransporter (hSGLT) inhibition.
- To compare the inhibitory effects of dapagliflozin, its analogs, and phlorizin on hSGLT1 and hSGLT2.
- To elucidate the structure-activity relationships governing inhibitor binding to SGLTs.
Main Methods:
- Electrophysiological methods were employed to assess transporter activity.
- hSGLT1 and hSGLT2 were expressed in human embryonic kidney 293T (HEK-293T) cells for functional studies.
- Inhibitory constants (K(i)) and dissociation rates (t(1/2,Off)) were determined for various inhibitors.
Main Results:
- Dapagliflozin and fluoro-dapagliflozin demonstrated ≈100-fold selectivity for hSGLT2 (K(i) = 6 nM) over hSGLT1 (K(i) = 400 nM).
- Galacto-dapagliflozin selectively inhibited hSGLT2 (K(i) = 25 nM) but was less potent against hSGLT1 (K(i) = 25,000 nM).
- Dapagliflozin and fluoro-dapagliflozin exhibited slower dissociation from hSGLT2 (t(1/2,Off) ≥ 180 s) compared to phlorizin and galacto-dapagliflozin (t(1/2,Off) ≈ 20-30 s).
Conclusions:
- Inhibitor binding to SGLTs is influenced by synergistic interactions between the sugar moiety and the aglycone.
- The flexibility of the glucose-binding site allows for conformational changes that affect aglycone orientation and binding affinity.
- Optimal pharmacophore design for SGLT inhibitors requires consideration of both sugar structure and aglycone variations.
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