2. Academic Validation
  3. Highly potent dipeptidyl peptidase 8/9 (DPP8/9) inhibitors designed via relative binding free energy calculations

Highly potent dipeptidyl peptidase 8/9 (DPP8/9) inhibitors designed via relative binding free energy calculations

  • Eur J Med Chem. 2025 Nov 5:297:117913. doi: 10.1016/j.ejmech.2025.117913.
Vanesa Nozal 1,  Olivier Beyens 2,  Sarah Peeters 2,  Adrian Fabisiak 2,  Koen Augustyns 2,  Ingrid De Meester 3,  Pieter Van Der Veken 2,  Hans De Winter 4
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium; Institut Químic de Sarrià (IQS), Universitat Ramon Llull, 08017, Barcelona, Spain. Electronic address: vanesa.nozal@iqs.url.edu.
  • 2 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • 3 Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium.
  • 4 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium. Electronic address: Hans.DeWinter@uantwerpen.be.
PMID: 40609224 DOI: 10.1016/j.ejmech.2025.117913
Abstract

Dipeptidyl peptidases (DPP) 8 and 9 are emerging enzymatic drug targets with suggested applications in acute myeloid leukaemia and HIV Infection, among Others. In this work, we optimised a well-known reference DPP8/9 inhibitor named 1G244, using relative binding free energy calculations. An initial retrospective, computational analysis of experimental structure-activity data of 1G244 and close structural analogues, guided the subsequent prospective design of novel inhibitors derived from the reference scaffold. Synthesis of the proposed compounds - together with in vitro evaluation and initial pharmacokinetic and pharmacodynamic studies - are presented and discussed. As a result, we present the optimization of 1G244 in a new family of potent piperidine based DPP8/9 inhibitors. Finally, we report for lead compound 21 and reference 1G244 the cardiac channel affinity which must be carefully considered when using these molecules as a tool to further clarify the role of DPP8 and DPP9 in cellular physiology.

Keywords

Dipeptidyl peptidase; Free energy perturbations; Inhibitor; hERG affinity.

Figures
Products