title: Structural modeling and docking studies of ribose 5-phosphate isomerase from Leishmania major and Homo sapiens: a comparative analysis for Leishmaniasis treatment.
abstract: Leishmaniases are caused by protozoa of the genus Leishmania and are considered the second-highest cause of death worldwide by parasitic infection. The drugs available for treatment in humans are becoming ineffective mainly due to parasite resistance; therefore, it is extremely important to develop a new chemotherapy against these parasites. A crucial aspect of drug design development is the identification and characterization of novel molecular targets. In this work, through an in silico comparative analysis between the genomes of Leishmania major and Homo sapiens, the enzyme ribose 5-phosphate isomerase (R5PI) was indicated as a promising molecular target. R5PI is an important enzyme that acts in the pentose phosphate pathway and catalyzes the interconversion of d-ribose-5-phosphate (R5P) and d-ribulose-5-phosphate (5RP). R5PI activity is found in two analogous groups of enzymes called RpiA (found in H. sapiens) and RpiB (found in L. major). Here, we present the first report of the three-dimensional (3D) structures and active sites of RpiB from L. major (LmRpiB) and RpiA from H. sapiens (HsRpiA). Three-dimensional models were constructed by applying a hybrid methodology that combines comparative and ab initio modeling techniques, and the active site was characterized based on docking studies of the substrates R5P (furanose and ring-opened forms) and 5RP. Our comparative analyses show that these proteins are structural analogs and that distinct residues participate in the interconversion of R5P and 5RP. We propose two distinct reaction mechanisms for the reversible isomerization of R5P to 5RP, which is catalyzed by LmRpiB and HsRpiA. We expect that the present results will be important in guiding future molecular modeling studies to develop new drugs that are specially designed to inhibit the parasitic form of the enzyme without significant effects on the human analog.
authors.affiliation: Grupo de Modelagem Molecular de Sistemas Biológicos, Laboratório Nacional de Computação Científica, GMMSB/LNCC-MCTI, Petrópolis, Brazil; Programa de Pós-graduação em Modelagem Computacional, Departamento de Ciência da Computação/Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora, PGMC/UFJF-MEC, Juiz de Fora, Brazil. Electronic address: priscila.capriles@ufjf.edu.br.
authors.forename: Priscila V S Z
authors.initials: PV
authors.lastname: Capriles
authors.affiliation: Grupo de Modelagem Molecular de Sistemas Biológicos, Laboratório Nacional de Computação Científica, GMMSB/LNCC-MCTI, Petrópolis, Brazil; Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, IOC/FIOCRUZ-MS, Rio de Janeiro, Brazil.
authors.forename: Luiz Phillippe R
authors.initials: LP
authors.lastname: Baptista
authors.affiliation: Grupo de Modelagem Molecular de Sistemas Biológicos, Laboratório Nacional de Computação Científica, GMMSB/LNCC-MCTI, Petrópolis, Brazil.
authors.forename: Isabella A
authors.initials: IA
authors.lastname: Guedes
authors.affiliation: Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, IOC/FIOCRUZ-MS, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Instituto Oswaldo Cruz, CDTS/FIOCRUZ-MS, Rio de Janeiro, Brazil.
authors.forename: Ana Carolina R
authors.initials: AC
authors.lastname: Guimarães
authors.affiliation: Grupo de Modelagem Molecular de Sistemas Biológicos, Laboratório Nacional de Computação Científica, GMMSB/LNCC-MCTI, Petrópolis, Brazil.
authors.forename: Fabio L
authors.initials: FL
authors.lastname: Custódio
authors.affiliation: Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, IOC/FIOCRUZ-MS, Rio de Janeiro, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Alves-Ferreira
authors.affiliation: Grupo de Modelagem Molecular de Sistemas Biológicos, Laboratório Nacional de Computação Científica, GMMSB/LNCC-MCTI, Petrópolis, Brazil. Electronic address: dardenne@lncc.br.
authors.forename: Laurent E
authors.initials: LE
authors.lastname: Dardenne
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D020134:Catalytic Domain; D006801:Humans; D007536:Isomerism; D018320:Leishmania major / Q000187:drug effects / Q000201:enzymology*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D012267:Ribosemonophosphates / Q000737:chemistry / Q000378:metabolism; D012274:Ribulosephosphates / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D040681:Structural Homology, Protein; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D008024:Ligands; D012267:Ribosemonophosphates; D012274:Ribulosephosphates; C031524:ribulose 5-phosphate; C031626:ribose-5-phosphate; D019747:Aldose-Ketose Isomerases; C022548:ribosephosphate isomerase
keywords: Homo sapiens; Leishmania major; Leishmaniasis treatment; Protein structure prediction; Protein–ligand docking; Ribose 5-phosphate isomerase