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.