Spatial and electronic features driving SGLT1/2 selectivity: a combined molecular dynamics and quantum mechanics...

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Rising global diabetes prevalence necessitates effective glucose regulation strategies.
• Selective sodium-glucose cotransporter (SGLT) inhibitors are crucial for managing diabetes.
• High sequence similarity between human SGLT1 and SGLT2 hinders selective inhibitor development.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying selective inhibition of SGLT1 and SGLT2.
• To identify key structural features dictating inhibitor selectivity between SGLT1 and SGLT2.
• To provide insights for the rational design of novel, highly selective SGLT inhibitors.

Main Methods:

• Microsecond-level molecular dynamics (MD) simulations of 22 SGLT protein-ligand complexes.
• Density Functional Theory (DFT) calculations on 97 highly selective inhibitors.
• Analysis of spatial complementarity, non-covalent interactions, and ligand charge distribution.

Main Results:

• Spatial complementarity between ligands and SGLT binding pockets is critical for selectivity.
• Specific interactions, like ASN78 with pyrazole substituents in SGLT1 inhibitors and GLN457 in SGLT2 inhibitors, determine selectivity.
• DFT and Hirshfeld charge analyses revealed stability, strength, and charge distribution differences influencing inhibitor behavior.

Conclusions:

• The study elucidates the selective inhibition mechanisms of SGLT1 and SGLT2 based on binding pocket differences.
• Key interactions and spatial arrangements provide a foundation for designing more effective and selective SGLT inhibitors.
• Computational approaches offer valuable insights for optimizing drug discovery in diabetes treatment.