title: Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies.
abstract: Babesia bigemina is a protozoan parasite that causes babesiosis, a disease with a world-wide distribution in mammals, principally affecting cattle and man. The unveiling of the genome of B. bigemina is a project in active progress that has already revealed a number of new targets with potential interest for the design of anti-babesiosis drugs. In this context, babesipain-1 has been identified as a proteolytically active enzyme whose three-dimensional structure has not been resolved yet, but which is known to be inhibited by cysteine proteases inhibitors such as E64, ALLN, leupeptin, and vinyl sulfones. In this work, we introduce (1) a homology model of babesipain-1; (2) a comparison between babesipain-1 and falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum; (3) in vitro data for babesipain-1 inhibition by HEDICINs and HECINs, previously reported as modest inhibitors of falcipain-2; and (4) the docked binding conformations of HEDICINs and HECINs in the model of babesipain-1. HEDICINs presented similar preferred binding conformations for both babesipain-1 and falcipain-2. However, in vitro bioassay shows that HEDICINs and HECINs are better inhibitors of babesipain-1 than of falcipain-2, which could be explained by observed differences between the active pockets of these proteins in silico. Results presented herein provide a valuable contribution to future computer-aided molecular design of new babesipain-1 inhibitors.
authors.affiliation: Departamento de Química, Faculdade de Ciências, Centro de Investigação em Química da Universidade do Porto, Universidade do Porto, R. Campo Alegre, 687, 4169-007, Porto, Portugal.
authors.forename: Bianca
authors.initials: B
authors.lastname: Pérez
authors.forename: Sandra
authors.initials: S
authors.lastname: Antunes
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Gonçalves
authors.forename: Ana
authors.initials: A
authors.lastname: Domingos
authors.forename: José R B
authors.initials: JR
authors.lastname: Gomes
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
authors.forename: Cátia
authors.initials: C
authors.lastname: Teixeira
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001403:Babesia / Q000201:enzymology* / Q000235:genetics; D002417:Cattle; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000737:chemistry; D057056:Cysteine Proteases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D057056:Cysteine Proteases; D003546:Cysteine Endopeptidases; C416224:falcipain 2