Rational Design and Molecular Docking-Based in Silico Affinity Analysis of Dioxabicyclo Octane Hybrids

AIM The aim of this study is to design, optimize, and evaluate novel dioxabicyclo[3.2.1]octane-based ligands as potential inhibitors of Sodium-Glucose Cotransporter 2 (SGLT2), thereby offering promising therapeutic alternatives for the management of type 2 diabetes mellitus. BACKGROUND The dioxabicyclo[3.2.1]octane moiety is a core structural feature of several SGLT2 inhibitors, including the FDA-approved drug ertugliflozin. The rigid, polycyclic architecture and modifiable bridgehead positions of this scaffold provide a versatile platform for structural modifications aimed at improving binding affinity, selectivity, and pharmacokinetic properties. EXPERIMENTAL WORK A total of 30 ligands were systematically designed with varying substitutions, including heteroatoms, functional groups, and fused rings. All ligands underwent energy minimization using the MMFF94 force field via Open Babel to obtain stable conformers. These optimized ligands were then subjected to molecular docking using AutoDock Vina against the SGLT2 receptor to evaluate their binding affinity. The best five compounds were further shortlisted based on docking scores and structural interactions. RESULTS & DISCUSSION Among the 30 ligands, Compound 24 (fused five-member N-heterocycle), Compound 25 (thiophene-fused ring), Compound 26 (fused imidazole), Compound 23 (six-membered aromatic fusion), and Compound 1 (parent scaffold) exhibited the most favorable binding affinities, ranging from –10.3 to –8.2 kcal/mol. These ligands also showed optimal RMSD values and energy-minimized conformations. Comparative analysis highlighted Compound 24 as the most promising SGLT2 inhibitor candidate. CONCLUSION This in silico study demonstrates the significance of scaffold modifications on the binding efficiency of dioxabicyclo derivatives toward SGLT2, paving the way for further experimental validation.