The Open Form Inducer Approach for Structure-Based Drug Design.

ABSTRACT: Many open form (OF) structures of drug targets were obtained a posteriori by analysis of co-crystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico) to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept

SUBMITTER: Inaoka DK 

PROVIDER: S-EPMC5125662 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature