Identification of new druggable sites based on the conformational analysis of the IDO1 enzyme for the rational design of new pharmacological inhibitors.

PATRICIO CHINESTREAD; MARIA ALEJANDRA ZINNI; RAMIRO BLANCO; ANA VELEZ RUEDA; MAIA CABRERA; PABLO LORENZANO MENNA

Viña del Mar

Conferencia; Fifth International Society for Computational Biology Latin America, SOIBIO and EMBnet Joint Bioinformatics Conference 2018 (ISCB-LA SOIBIO EMBnet 2018); 2018

ISCB-LA SOIBIO

Indoleamine-2,3-dioxygenase 1 (IDO1) is an enzyme of the cellular metabolism of tryptophan (Trp), responsible for the conversion of Trp to kynurenine (Kyn). The overactivation of this enzyme has been linked to the escape process of tumor cells from the immune system regulation (immunoediting). For these reasons, IDO1 has become a highly attractive target for the development of new therapeutic strategies against cancer.In this work, we characterize IDO1 structurally to explore new inhibition targets for the rational design of novel inhibitors. For this end we studied the experimentally available conformational diversity (e.g. XR) of IDO1 assessing the variations of quantity and physicochemical features of cavities and tunnels from said conformers. Based on this analysis we were able to characterize active and inactive conformations. We could determine conformation patterns specific to the inactive conformations, that were missing in the active conformations, and therefore could be relevant as inhibition targets. Also, using redocking studies with ligands crystalized at the active site, we observed a marked decrease in binding energies of said compounds to the active site; being nearly 25% lower for the inactive conformations (-6.3 ± 0.36 kJ) as opposed to the active conformations (-8.2 ± 0.47 kJ).Our results suggest that the presence of druggable cavities specific to the inactive conformations would make the development of novel inhibitors possible, and also asses the study of conformational features as a possible way for new pharmacological targets prediction positively, and offers unique structural features for the design of clinically relevant IDO1 inhibitors.