Toward the discovery of inhibitors of babesipain-1, a Babesia bigemina cysteine protease: in vitro evaluation, homology modeling and molecular docking studies

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Bianca Perez (Author) Other; Sandra Antunes (Author) Other; Lidia M Goncalves (Author) Other; Ana Domingos (Author) Other; Jose R B Gomes (Author) Other; Paula Gomes (Author) FCUP; Catia Teixeira (Author) Other

Journal

Title: Journal of Computer-Aided Molecular Design

Vol. 27

Pages: 823-835

ISSN: 0920-654X

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 10 Citations

Scopus - 10 Citations

Scientific classification

FOS: Natural sciences > Computer and information sciences

Other information

Authenticus ID: P-006-7D9

DOI: 10.1007/s10822-013-9682-2

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific