title: Discovery of small molecule inhibitors for the snake venom metalloprotease BaP1 using in silico and in vitro tests.
abstract: Snakebites represent an important public health problem, with a great number of victims with permanent sequelae or fatal outcomes, particularly in rural, agriculturally active areas. The snake venom metalloproteases (SVMPs) are the principal proteins responsible for some clinically-relevant effects, such as local and systemic hemorrhage, dermonecrosis, and myonecrosis. Because of the difficulties in neutralizing them rapidly and locally by antivenoms, the search and design of small molecules as inhibitors of SVMPs are proposed. The Bothrops asper metalloprotease P1 (BaP1) is hereby used as a target protein and by High Throughput Virtual Screening (HTVS) approach, the free access virtual libraries: ZINC, PubChem and ChEMBL, were searched for potent small molecule inhibitors. Results from the aforementioned approaches provided strong evidences on the structural requirements for the efficient BaP1 inhibition such as the presence of the pyrimidine-2,4,6-trione moiety. The two proposed compounds have also shown excellent results in performed in vitro interaction studies against BaP1.
authors.affiliation: Chemical Biology Laboratory, Organic Chemistry Department, Institute of Chemistry, UNICAMP, Campinas, SP, Brazil.
authors.forename: Fabian
authors.initials: F
authors.lastname: Villalta-Romero
authors.affiliation: Institute of Biology, UNICAMP, Campinas, SP, Brazil.
authors.forename: Luiz
authors.initials: L
authors.lastname: Borro
authors.affiliation: Chemical Biology Laboratory, Organic Chemistry Department, Institute of Chemistry, UNICAMP, Campinas, SP, Brazil; Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
authors.forename: Boris
authors.initials: B
authors.lastname: Mandic
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Teresa
authors.initials: T
authors.lastname: Escalante
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rucavado
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Jose María
authors.initials: JM
authors.lastname: Gutiérrez
authors.affiliation: Brazilian Agricultural Research Corporation (EMBRAPA), National Center for Agricultural Informatics, Computational Biology Research Group, Campinas, SP, Brazil.
authors.forename: Goran
authors.initials: G
authors.lastname: Neshich
authors.affiliation: Chemical Biology Laboratory, Organic Chemistry Department, Institute of Chemistry, UNICAMP, Campinas, SP, Brazil. Electronic address: ljubica@iqm.unicamp.br.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Tasic
mesh_terms: D000818:Animals; D000931:Antidotes / Q000737:chemistry* / Q000494:pharmacology*; D017837:Bothrops / Q000378:metabolism*; D003198:Computer Simulation; D055808:Drug Discovery; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D012910:Snake Venoms / Q000037:antagonists & inhibitors*
chemical_list: D000931:Antidotes; D011744:Pyrimidinones; D054852:Small Molecule Libraries; D012910:Snake Venoms; C000620878:pyrimidine-2,4,6-trione; C104933:BaP1 metalloproteinase; D008666:Metalloendopeptidases
keywords: BaP1; High Through Virtual Screening; Inhibitors; Snake venom metalloproteases; in vitro interaction studies