title: Oligopeptidase B and B2: comparative modelling and virtual screening as searching tools for new antileishmanial compounds.
abstract: Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis.
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
authors.forename: Ana Carolina R
authors.identifier: 0000-0002-2603-1740
authors.initials: AC
authors.lastname: Sodero
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
authors.forename: Ana Carolina G O
authors.initials: AC
authors.lastname: Dos Santos
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
authors.forename: Juliana F R E
authors.initials: JF
authors.lastname: Mello
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
authors.forename: Jéssica B
authors.initials: JB
authors.lastname: DE Jesus
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: DE Souza
authors.affiliation: Centro de Desenvolvimento Tecnológico em Saúde (CDTS)/Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN),21045-900 Rio de Janeiro, RJ,Brazil.
authors.forename: Maria Isabel C
authors.initials: MI
authors.lastname: Rodrigues
authors.affiliation: Centro de Desenvolvimento Tecnológico em Saúde (CDTS)/Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN),21045-900 Rio de Janeiro, RJ,Brazil.
authors.forename: Salvatore G
authors.initials: SG
authors.lastname: DE Simone
authors.affiliation: Laboratório de Modelagem Molecular e QSAR (MODMOLQSAR),Departamento de Fármacos e Medicamentos,Universidade Federal do Rio de Janeiro (UFRJ),Av. Carlos Chagas Filho,373, 21941-599,Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: Grupo de Imunologia e Vacinologia, Laboratório de Inflamação,Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro,21941-902 Rio de Janeiro, RJ,Brazil.
authors.forename: Herbert L
authors.initials: HL
authors.lastname: DE Matos Guedes
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D016208:Databases, Factual; D015971:Gene Expression Regulation, Enzymologic; D007891:Leishmania / Q000201:enzymology*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012984:Software
chemical_list: D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases
keywords: Leishmaniasis; docking; oligopeptidase; virtual screening