title: Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors.
abstract: Leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm = 11 °C, p = 0,01). Kinetic assays reveal that 2d has IC50 = 44.67 ± 1.74 μM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50 000 ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors.
authors: Programa de Pós-graduação em Biotecnologia - PPGBiotec, Universidade Estadual de Feira de Santana, Brazil.
authors: Franco Henrique A
authors: FHA
authors: Leite
authors: Departamento de Antibióticos, Universidade Federal de Pernambuco, Brazil.
authors: Priscila Brandão Gomes da Silva
authors: PBGDS
authors: Santiago
authors: Faculdade de Farmácia, Universidade Federal da Bahia, Brazil.
authors: Thamires Quadros
authors: TQ
authors: Froes
authors: Departamento de Antibióticos, Universidade Federal de Pernambuco, Brazil.
authors: João
authors: J
authors: da Silva Filho
authors: Faculdade de Farmácia, Universidade Federal da Bahia, Brazil.
authors: Suellen Gonçalves
authors: SG
authors: da Silva
authors: Departamento de Antibióticos, Universidade Federal de Pernambuco, Brazil.
authors: Rafael M
authors: RM
authors: Ximenes
authors: Departamento de Farmácia, Universidade Federal de Pernambuco, Brazil.
authors: Antônio Rodolfo
authors: AR
authors: de Faria
authors: Departamento de Farmácia, Universidade Federal de Pernambuco, Brazil.
authors: Dalci José
authors: DJ
authors: Brondani
authors: Departamento de Antibióticos, Universidade Federal de Pernambuco, Brazil.
authors: Julianna F C
authors: JFC
authors: de Albuquerque
authors: Programa de Pós-graduação em Biotecnologia - PPGBiotec, Universidade Estadual de Feira de Santana, Brazil; Faculdade de Farmácia, Universidade Federal da Bahia, Brazil. Electronic address: castilho@ufba.br.
authors: Marcelo Santos
authors: MS
authors: Castilho
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D018320:Leishmania major / Q000201:enzymology*; D008958:Models, Molecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; D010088:Oxidoreductases; C085592:pteridine reductase
keywords: Kinetic assay; Leishmania; Molecular modeling; Pteridine reductase 1; Thermal shift assay; Thiazolidine-2,4-dione derivatives