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Bioorg Med Chem Lett. 2017 May 1;27(9):2018-2022. doi: 10.1016/j.bmcl.2017.03.007. Epub 2017 Mar 6.

Discovery of small molecule inhibitors for the snake venom metalloprotease BaP1 using in silico and in vitro tests.

Author information

1
Chemical Biology Laboratory, Organic Chemistry Department, Institute of Chemistry, UNICAMP, Campinas, SP, Brazil.
2
Institute of Biology, UNICAMP, Campinas, SP, Brazil.
3
Chemical Biology Laboratory, Organic Chemistry Department, Institute of Chemistry, UNICAMP, Campinas, SP, Brazil; Faculty of Chemistry, University of Belgrade, Belgrade, Serbia.
4
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
5
Brazilian Agricultural Research Corporation (EMBRAPA), National Center for Agricultural Informatics, Computational Biology Research Group, Campinas, SP, Brazil.
6
Chemical Biology Laboratory, Organic Chemistry Department, Institute of Chemistry, UNICAMP, Campinas, SP, Brazil. Electronic address: ljubica@iqm.unicamp.br.

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.

KEYWORDS:

BaP1; High Through Virtual Screening; Inhibitors; Snake venom metalloproteases; in vitro interaction studies

PMID:
28347665
DOI:
10.1016/j.bmcl.2017.03.007
[Indexed for MEDLINE]

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