INVESTIGADORES
ENRIZ Ricardo Daniel
artículos
Título:
A molecular Modeling Study of new inhibitors of Dihydrofolate Reductase. MD simulations, QM calculations and experimental corroboration
Autor/es:
R. TOSSO; S. ANDUJAR; E,ANGELINA; R.RODRIGUEZ; M.NOGUERAS; H. BALDONI; F.SUVIRE; J.COBO; ENRIZ R.D.
Revista:
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Editorial:
AMER CHEMICAL SOC
Referencias:
Lugar: Washington; Año: 2013 vol. 53 p. 2018 - 2032
ISSN:
1549-9596
Resumen:
A molecular modeling study on dihydrofolate reductase
(DHFR) inhibitors was carried out. By combining molecular dynamics
simulations with semiempirical (PM6), ab initio, and density functional
theory (DFT) calculations, a simple and generally applicable procedure
to evaluate the binding energies of DHFR inhibitors interacting with the
human enzyme is reported here, providing a clear picture of the binding
interactions of these ligands from both structural and energetic
viewpoints. A reduced model for the binding pocket was used. This
approach allows us to perform more accurate quantum mechanical
calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus,
molecular aspects of the binding interactions between inhibitors and the
DHFR are discussed in detail. A significant correlation between binding
energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper