Study of the MDM2- p53 complex and small-molecule inhibitory their interaction

MENENDEZ C.A; ACCORDINO S.A; APPIGNANESI G.A; GERBINO D.C

Sierra de la Ventana

Congreso; XLIII Reunión Anual de la Sociedad Argentina de Biofísica; 2014

Sociedad Argentina de Biofísica

The aim of study of this work is the binding site of MDM2 protein with tumor suppressor p53, as well as the interaction between MDM2 with disruptive molecules as nutlin and different xanthones, focusing our interest in principle in the 3,4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one.(1) The latter are part of a novel family of oxygenated heterocycles, found in nature in various species of fungi, algae and higher plants. The study of such compounds is of great interest because they possess interesting biological activities with potential therapeutic applications. Using molecular dynamics studies was possible to establish which are presumably three fundamental positions in the binding site of MDM2 is necessary "to cover." In these positions the natural "partner" (p53) accommodates hydrophobic residues, behavior that is mimicked by nutlin. The xanthone studied also binds to the same site or "hot spot", but only has the ability to cover two of these positions simultaneously, reason that adopts different conformations along time, alternating their interaction with those positions. From these results it would be possible to rationally functionalize this prototype and achieve an increase in its activity as an inhibitor of the MDM2-p53 interaction.