Clinical informatics and molecular hybridization of established clinical DPP-4 inhibitors to generate next-level diabetes type 2 drugs

Diabetes mellitus, often known as hyperglycemia, is a serious worldwide disease now. In clinical pharmacology, the dipeptidyl peptidase IV (DPP-4) enzyme is important for glucose homeostasis. The clinical DPP-4 blockers are essential oral antidiabetic medications used as alternate treatment following metformin inability as insulinotropic drugs with no inherent risk of hypoglycemia. The objective of this study is to create novel and potent DPP-4 inhibitors by molecular hybridization of eight clinically licensed DPP-4 inhibitors. Molecular hybridization process led to the creation of five novel hybridized DPP-4 inhibitors, which preliminary computational studies suggest may exhibit improved selectivity compared to authorized DPP-4 inhibitors. The pharmacokinetic features of the hybridized inhibitors, including their solubility and potential to pass through biological tissues, were evaluated using Lipinski’s rule of five and other druglikeness filters, indicating favorable properties for reaching the DPP-4 active site. Furthermore, the possible toxicity of suggested inhibitors was investigated using basic toxicity filters and PASS, indicating no immediate red flags regarding their potential toxicity and metabolism. In addition, a mechanism for synthesizing the proposed compounds has been developed via machine learning and artificial intelligence algorithms. At the biomolecular level, using the Gromacs package, molecular dynamics simulations (100 ns) were performed for all the studied systems. Following analyzing the molecular dynamics trajectories and evaluating the dynamic shifts of DPP-4 after its molecular interactions with the designed compounds via dynamic cross-correlation matrix, free energy landscape and MM-PBSA calculations, all data show that the proposed DPP-4 inhibitors create extremely stable complexes when compared to the clinical DPP-4 inhibitor (alogliptin). Finally, the findings of this study might greatly contribute to the development of novel and potent DPP-4 inhibitors and assist in the search for new medications for diabetes type 2.

Graphical abstract