MARINE PHLOROTANNINS AS LEAD CANDIDATES FOR DPP-4 INHIBITION: A COMPUTATIONAL DRUG DISCOVERY PIPELINE EVALUATION FOR TYPE 2 DIABETES THERAPEUTICS

Abstract

The worldwide diabetes pandemic of Type 2 diabetes mellitus (T2DM) has become the most common metabolic disease which affects global populations as the number of affected individuals is expected to reach 700 million people by 2045. Dipeptidyl peptidase-4 (DPP-4) inhibitors, or gliptins, have emerged as an important pharmacological class for T2DM management by extending the bioavailability of endogenous glucagon-like peptide-1 (GLP-1). The three gliptins that exist on the market include sitagliptin and saxagliptin and linagliptin but these medications cause harmful effects and create financial difficulties for patients in low- and middle-income countries. This situation creates a need to study natural products because they might provide better safety and cheaper development expenses.

Marine phlorotannins function as a unique type of polyphenolic compound which brown algae from the class Phaeophyceae use to create their own biosynthetic pathways. Marine phlorotannins show multiple biological activities which include their ability to fight diabetes and reduce inflammation and their antioxidant properties. The research team has not yet conducted a complete investigation into marine phlorotannins as potential lead substances for drug development.

The thesis establishes an entire in silico drug discovery process assessment for five marine phlorotannins which include phloroglucinol, eckol, dioxinodehydroeckol, fucodiphloroethol G, and phlorofucofuroeckol A as they interact with DPP-4 found in humans. Through AutoDock Vina molecular docking which operates with PyRx software phlorofucofuroeckol A showed the strongest binding capacity because it achieved a binding energy of −10.2 kcal/mol which exceeded the binding energy of the FDA-approved drug sitagliptin which reached −9.2 kcal/mol. The protein ligand interaction analysis showed that BIOVIA Discovery Studio confirmed permanent binding with the DPP-4 active site through Glu205 Glu206 Tyr662 Tyr666 Trp659 catalytic residues.

The researchers conducted extensive computational ADMET testing through SwissADME and pkCSM to evaluate all candidate phlorotannins. The drug-like properties of Phlorofucofuroeckol A meet both Lipinski and Veber standards and it shows predicted oral bioavailability which is considered acceptable together with a safe toxicity profile. The comparative assessment between this marine natural product and sitagliptin shows its potential for practical application. The combined research results establish phlorofucofuroeckol A as a strong candidate for molecular dynamics simulations and in vitro enzymatic validation studies.