Potential DPP-IV inhibitors for type 2 diabetes mellitus: an integrated computational and experimental pipeline
7 affiliations
- 1Pediatric Research Institute, Children’s Hospital Affiliated to Shandong University (Jinan Children’s Hospital)
- 2Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University
- 3Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk
- 4Department of Biochemistry, College of Science, King Saud University
- 5Clinical Biochemistry Unit, Department of Pathology, College of Medicine, King Saud University
- 6Innovation Ecosystem, King Khalid University
- 7Department of Medical Laboratories Sciences, College of Applied Medical Sciences in Alquwayiyah, Shaqra University
Abstract
Dipeptidyl peptidase-IV (DPP-IV) inhibition remains a cornerstone therapeutic strategy for managing type 2 diabetes mellitus (T2DM) by prolonging endogenous incretin hormone activity. However, developing next-generation inhibitors with optimized pharmacokinetic profiles and enhanced target stability remains an ongoing challenge. This study presents a comprehensive, multi-tiered evaluation of gosogliptin and novel PubChem-derived DPP-IV inhibitors (e.g., PubChem 11450633, PubChem 46216692) compared to the clinical benchmark, sitagliptin. Extensive 300-ns molecular dynamics (MD) simulations and MM-GBSA calculations revealed that compounds PubChem 11,450,633 and PubChem 46,216,692 exhibit superior thermodynamic stability and binding affinities (Delta G bind = -48.77 and − 46.76 kcal/mol, respectively) compared to sitagliptin (-44.46 kcal/mol). This outperformance is driven by optimal van der Waals packing, robust electrostatic anchoring to the Glu205/Glu206 dyad, and balanced polar desolvation penalties. In silico ADMET profiling confirmed favorable drug-likeness, high gastrointestinal absorption, and negligible blood-brain barrier permeation. Experimental validation strongly corroborated these computational predictions. Gosogliptin demonstrated a 2.5-fold higher aqueous solubility (0.30 mg/mL) than sitagliptin (0.12 mg/mL) alongside a highly favorable, low-lipophilicity profile (experimental LogP = 0.30). In cell-based functional assays, gosogliptin achieved equipotent GLP-1 protection (around 75% at 100 nM) and exhibited an exceptional safety margin, maintaining cell viability up to 50 micromolar. Collectively, these synergistic computational and experimental findings highlight gosogliptin and specific lead candidates as highly promising, safe, and efficacious DPP-IV inhibitors. The optimized pharmacokinetic and thermodynamic profiles demonstrated in this study strongly warrant their advancement into in vivo preclinical models for next-generation T2DM therapeutics.
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BibTeX
@article{abdalla2026potential,
title = {{Potential DPP-IV inhibitors for type 2 diabetes mellitus: an integrated computational and experimental pipeline}},
author = {Mohnad Abdalla and Guiyu Lin and Mohamed T. M. Nemr and Abdullah Hamadi and Nouf Omar AlAfaleq and Khalid M. Sumaily and Essa M. Sabi and Ahmed H. Mujamammi and Jameel Barnawi and Amr Ahmed El-Arabey and Ziyad M. Althafar and Yongsheng Ge and Guohua Liu},
journal = {Scientific Reports},
year = {2026},
month = sep,
doi = {10.1038/s41598-026-70309-8},
url = {https://doi.org/10.1038/s41598-026-70309-8},
note = {CC BY},
}
RIS
TY - JOUR
TI - Potential DPP-IV inhibitors for type 2 diabetes mellitus: an integrated computational and experimental pipeline
AU - Mohnad Abdalla
AU - Guiyu Lin
AU - Mohamed T. M. Nemr
AU - Abdullah Hamadi
AU - Nouf Omar AlAfaleq
AU - Khalid M. Sumaily
AU - Essa M. Sabi
AU - Ahmed H. Mujamammi
AU - Jameel Barnawi
AU - Amr Ahmed El-Arabey
AU - Ziyad M. Althafar
AU - Yongsheng Ge
AU - Guohua Liu
PY - 2026
DA - 2026/09/01
JO - Scientific Reports
DO - 10.1038/s41598-026-70309-8
UR - https://doi.org/10.1038/s41598-026-70309-8
AB - Dipeptidyl peptidase-IV (DPP-IV) inhibition remains a cornerstone therapeutic strategy for managing type 2 diabetes mellitus (T2DM) by prolonging endogenous incretin hormone activity. However, developing next-generation inhibitors with optimized pharmacokinetic profiles and enhanced target stability remains an ongoing challenge. This study presents a comprehensive, multi-tiered evaluation of gosogliptin and novel PubChem-derived DPP-IV inhibitors (e.g., PubChem 11450633, PubChem 46216692) compared to the clinical benchmark, sitagliptin. Extensive 300-ns molecular dynamics (MD) simulations and MM-GBSA calculations revealed that compounds PubChem 11,450,633 and PubChem 46,216,692 exhibit superior thermodynamic stability and binding affinities (Delta G bind = -48.77 and − 46.76 kcal/mol, respectively) compared to sitagliptin (-44.46 kcal/mol). This outperformance is driven by optimal van der Waals packing, robust electrostatic anchoring to the Glu205/Glu206 dyad, and balanced polar desolvation penalties. In silico ADMET profiling confirmed favorable drug-likeness, high gastrointestinal absorption, and negligible blood-brain barrier permeation. Experimental validation strongly corroborated these computational predictions. Gosogliptin demonstrated a 2.5-fold higher aqueous solubility (0.30 mg/mL) than sitagliptin (0.12 mg/mL) alongside a highly favorable, low-lipophilicity profile (experimental LogP = 0.30). In cell-based functional assays, gosogliptin achieved equipotent GLP-1 protection (around 75% at 100 nM) and exhibited an exceptional safety margin, maintaining cell viability up to 50 micromolar. Collectively, these synergistic computational and experimental findings highlight gosogliptin and specific lead candidates as highly promising, safe, and efficacious DPP-IV inhibitors. The optimized pharmacokinetic and thermodynamic profiles demonstrated in this study strongly warrant their advancement into in vivo preclinical models for next-generation T2DM therapeutics.
SN - 2045-2322
ER -