Highly potent dipeptidyl peptidase 8/9 (DPP8/9) inhibitors designed via relative binding free energy calculations
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...
| Autores: | , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:20.500.14342/5710 |
| Acceso en línea: | http://hdl.handle.net/20.500.14342/5710 https://doi.org/10.1016/j.ejmech.2025.117913 |
| Access Level: | acceso embargado |
| Palabra clave: | Free energy perturbations Dipeptidyl peptidase Inhibitor hERG affinity Antigen CD26--Inhibidors CD26 antigen--Inhibidors 577 |
| Sumario: | 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. |
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