STRUCTURE ACTIVITY RELATIONSHIP ANALYSIS OF MARINE PHLOROTANNINS AS SELECTIVE DPP-4 INHIBITORS: A COMPUTATIONAL PERSPECTIVE

Abstract

T2DM is a metabolic disorder affecting hundreds of thousands of people globally, characterized by insulin secretion and insulin resistance. DPP-4) has emerged as a clinically important pharmacological target in T2DM management, as its inhibition increases the half life of the hormone GLP-1, thereby enhancing insulin secretion. While synthetic DPP-4 inhibitors are clinically approved, their long-term use is associated with heart and pulmonary problems, along with high costs in developing countries. These problems have made it necessary to explore natural sources as inhibitors of DPP-4. Marine phlorotannins, natural phenolic compounds derived from brown algae, have demonstrated broad-spectrum activities including anti-diabetic, anti-inflammatory, and antioxidant properties. This thesis specifically investigates the SAR of five marine phlorotannins: phloroglucinol, eckol, dioxinodehydroeckol, fucodiphloroethol G, and phlorofucofuroeckol A as potential inhibitors of DPP-4, using in silico molecular docking as the tool of interest. Molecular docking was done using the AutoDock Vina algorithm via the PyRx virtual screening tool. The DPP-4 structure was obtained from the RCSB Protein Data Bank, and the ligand structure from PubChem. interactions between P-L were analyzed using BIOVIA Discovery Studio Visualizer, with a focus on interactions involving the catalytic residues Glu205, Glu206, Tyr662, Tyr666, and Trp659. The SAR analysis reveals a strong positive correlation between phlorotannin’s structural complexity, specifically the degree of polymerization, number of hydroxyl groups, and extent of aromatic ring fusion with binding affinity for DPP-4. Phlorofucofuroeckol A, the most complex compound studied, achieved the binding affinity of (−10.2 kcal/mol), better than the synthetic control sitagliptin (−9.2 kcal/mol). Further SAR analysis with different structural series shows that an increment in ring complexity corresponds to improvements in binding energy, selectivity of active-site engagement, and interaction with both the S1 and S2 substrate binding subsites.