Exploration of Novel Type 2 Antidiabetic Agents: Molecular Docking and Toxicity Assessment of Polyphenolic Compounds for Improved Therapeutic Potential

Type 2 diabetes (DM2) poses significant global health challenges due to insulin resistance andimpaired glucose metabolism. Dipeptidyl peptidase-4 (DPP4) inhibitors are keypharmacological agents used to manage DM2, but concerns over side effects prompt explorationof alternative therapies. This study investigates the potential of polyphenolic compounds asnovel inhibitors of the dipeptidyl peptidase-4 (DPP4) enzyme for type 2 diabetes management.Polyphenolic ligands, including 3,4-Dicaffeoylquinic Acid, Apiin, Naringin, Cirsiliol,Cryptochlorogenic Acid, Cirsilineol, and Quercitrin, were subjected to molecular docking withthe DPP4 receptor for the first time using Molecular Operating Environment (MOE) software.Our analysis reveals compelling binding interactions, with several ligands demonstrating notablylow docking scores compared to synthetic inhibitors. Notably, 3,4-Dicaffeoylquinic Acid, Apiin,and Naringin exhibited docking scores of -7.7, -7.6, and -7.4, respectively, surpassingestablished synthetic inhibitors Sitagliptin (-7.4), Vildagliptin (-6.6), and Saxagliptin (-5.9).Furthermore, a toxicity assessment of the polyphenolic ligands showed elevated LD50 values,emphasizing their potential safety. Quinic Acid, 3,4-Dicaffeoylquinic Acid, and Apiindemonstrated LD50 values of 9800 mg/kg, 5000 mg/kg, and 5000 mg/kg, respectively, with hightoxicity classes indicative of a favourable safety profile. This study signifies a significantadvancement in exploring alternative therapies for type 2 diabetes, underscoring the promisingefficacy and safety of polyphenolic ligands as potential DPP4 inhibitors. The findings highlightthe transformative potential of these natural compounds in reshaping diabetes therapeutics andwarrant further investigation into their molecular mechanisms and therapeutic applications.