A computer-driven scaffold-hopping approach generating new PTP1B inhibitors from the pyrrolo[1,2-a]quinoxaline core

13 p.-9 fig.-3 tab.Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold-hopping approach to vary the pyrrole ring of the pyrrolo[1,2-a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end-point free-energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.We are grateful for funding from the Spanish Ministerio de Economía y Competitividad (CTQ2017-85263-R MINECO/FEDER UE to J.J.V.); Instituto de Salud Carlos III and FEDER funds (RD16/0009/0015, RD16/0009/18, PI17/01513 and PI17/00625 to J.J.V., D.R.-P. and M.R.-P.). J. G−M was the recipient of an FPU fellowship (FPU16/01647) Spanish Ministerio de Educación y Cultura.Peer reviewe