A drug repurposing-based investigation of USFDA-approved anticancer drugs towards dipeptidyl-peptidase 4 (DPP4) receptor inhibition: An in silico and in vitro investigation to treat diabetes and associated conditions

Abstract

Dipeptidyl-peptidase 4 (DPP4) is a central molecular target that is known to be associated both with type 2 diabetes (T2DM) and cancer. The association of DPP4 in cancer is ever-expanding, with a plethora of evidence and clinical trials being instigated to find a plausible cure. The literature shows that DPP4 inhibitors could overcome the drug resistance associated with cancer chemotherapy, diminish the plausibility of secondary oncogenesis, activate the immune system against the cancer cells, and simultaneously halt cancer stemness. However, since drug discovery is a long, time-consuming, and costly affair, we limited ourselves to applying drug repositioning, which is an emerging thrust area of cost and time-effective drug discovery. We put the present research considering the benefit associated with incorporating DPP4 inhibitors in cancer regimens, or the patients suffering from cancer with high expression of DPP4, or considering the plausibility of diabetes prognosis to cancer. In the present work, we took 110 targeted anticancer agents approved by the US-FDA and filtered them through the developed pharmacophore model of DPP4. The top ligands resembling pharmacophores were further subjected to molecular docking and molecular mechanics experiments. The thorough analysis led us to identify five ligands with the highest affinity for the DPP4 receptor. The top-scoring ligand, palbociclib, was further subjected to molecular dynamics analysis, and its DPP4 inhibition was corroborated using an ELISA-based DPP4 assay on a MIN-6 cell line. The present work thus opens up the avenues to further explore the utility of the identified drug in depth using a plethora of in vitro and in vivo studies and delineate its molecular mechanisms.