Molecular Design Strategies and QSAR-Based Assessment of Synthesized Heterocycles for Diabetes Management

Abstract

Diabetes mellitus (DM) represents a critical global metabolic disorder, with an estimated 537 million adults affected worldwide as of 2021. The present study evaluates the molecular design strategies and quantitative structure-activity relationship (QSAR)-based assessment of synthesized heterocyclic scaffolds, including thiazolidinediones, triazoles, oxadiazoles, coumarins, and pyrimidines, as potential antidiabetic agents targeting key enzymes such as α-glucosidase, α-amylase, DPP-IV, and PTP-1B. The objective was to correlate structural descriptors of heterocyclic compounds with their biological activity (IC₅₀) through validated QSAR models and molecular docking studies. A computational methodology integrating 2D/3D-QSAR modeling, pharmacophore mapping, and molecular docking was employed on datasets of synthesized heterocycles reported between 2015 and 2021. The hypothesis posited that electron-withdrawing substituents and hydrogen bond donor/acceptor features on heterocyclic scaffolds significantly enhance antidiabetic potency. Results demonstrated that QSAR models achieved strong statistical validity (R² > 0.85, Q² > 0.60), and docking scores confirmed favorable binding interactions with target proteins. The thiazolidinedione-triazole and coumarin-based hybrids exhibited the most potent IC₅₀ values. In conclusion, QSAR-guided molecular design provides a robust framework for optimizing heterocyclic leads, and future synthesis efforts should prioritize halogen and methoxy substitutions on these scaffolds for enhanced antidiabetic efficacy.