Publications > García-Marín et al
A Computer-Driven Scaffold-Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2-a]quinoxaline Core.
1. Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28805, Alcalá de Henares, Spain. 2. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034, Madrid, Spain. 3. Instituto de Investigación Química Andrés Manuel del Río (IQAR), Universidad de Alcalá, Alcalá de Henares, Spain. 4. Departamento de Química Biológica y Estructural, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Calle Ramiro de Maeztu 9, 28040, Madrid, Spain. 5. Graphenano Medical Care, S.L., C/Pablo Casals, no. 13, Yecla, Murcia, Spain. 6. Departamento de Biología de Sistemas, Universidad de Alcalá, 28805, Alcalá de Henares, Spain.
Keywords: MM-ISMSA; PTP1B, phosphatase; glucose uptake; molecular dynamics; molecular modelling; pyrrolo[1,2-a]quinoxaline; scaffold hopping
Abstract
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.