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

Abstract

Type 2 diabetes (DM2) poses significant global health challenges due to insulin resistance and impaired glucose metabolism. Dipeptidyl peptidase-4 (DPP4) inhibitors are key pharmacological agents used to manage DM2, but concerns over side effects prompt exploration of alternative therapies. This study investigates the potential of polyphenolic compounds as novel 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 with the DPP4 receptor for the first time using Molecular Operating Environment (MOE) software. Our analysis reveals compelling binding interactions, with several ligands demonstrating notably low 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, surpassing established 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 Apiin demonstrated LD50 values of 9800 mg/kg, 5000 mg/kg, and 5000 mg/kg, respectively, with high toxicity classes indicative of a favourable safety profile. This study signifies a significant advancement in exploring alternative therapies for type 2 diabetes, underscoring the promising efficacy and safety of polyphenolic ligands as potential DPP4 inhibitors. The findings highlight the transformative potential of these natural compounds in reshaping diabetes therapeutics and warrant further investigation into their molecular mechanisms and therapeutic applications.