title: Discovery of new potential hits of Plasmodium falciparum enoyl-ACP reductase through ligand- and structure-based drug design approaches.
abstract: We here report the discovery of novel Plasmodium falciparum enoyl-ACP reductase (PfENR) inhibitors as new antimalarial hits through ligand- and structure-based drug design approaches. We performed 2D and 3D QSAR studies on a set of rhodanine analogues using hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Statistical and satisfactory results were obtained for the best HQSAR (r(2) of 0.968 and qLOO(2) of 0.751), CoMFA (r(2) of 0.955 and qLOO(2) of 0.806) and CoMSIA (r(2) of 0.965 and qLOO(2) of 0.659) models. The information gathered from the QSAR models guided us to design new PfENR inhibitors. Three new hits were predicted with potency in the submicromolar range and presented drug-like properties.
authors.affiliation: Laboratório de Planejamento de Fármacos e Estudos de Metabolismo por Modelagem Molecular, Faculdade de Farmácia, Universidade Federal de Goiás, Praça Universitária com 1a Av, Goiânia GO 74605-220, Brazil.
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Neves
authors.forename: Renata V
authors.initials: RV
authors.lastname: Bueno
authors.forename: Rodolpho C
authors.initials: RC
authors.lastname: Braga
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D055808:Drug Discovery; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D008024:Ligands; D012236:Rhodanine; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)