A molecular modeling study of receptor-ligand complexes using MD simulations and QM calculations.

ANDUJAR SEBASTIAN

San Miguel de Tucuman

Conferencia; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012

Sociedad Argentina de Biofísica

A molecular modeling study on dihydrofolate reductase(DHFR) inhibitors was carried out. By combining molecular dynamicssimulations with semiempirical (PM6), ab initio, and density functionaltheory (DFT) calculations, a simple and generally applicable procedureto evaluate the binding energies of DHFR inhibitors interacting with thehuman enzyme is reported here, providing a clear picture of the bindinginteractions of these ligands from both structural and energeticviewpoints. A reduced model for the binding pocket was used. Thisapproach allows us to perform more accurate quantum mechanicalcalculations as well as to obtain a detailed electronic analysis using thequantum theory of atoms in molecules (QTAIM) technique. Thus,molecular aspects of the binding interactions between inhibitors and theDHFR are discussed in detail. A significant correlation between bindingenergies 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.