Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

Pérez, Bianca; Teixeira, Cátia; Figueiras, Marta; Gut, Jiří; Rosenthal, Philip J.; Gomes, J.R.; Gomes, Paula

doi:10.1016/j.ejmech.2012.05.022

Cited by 54 publications

(49 citation statements)

References 58 publications

(64 reference statements)

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“…9a). A similar conformation was previously obtained when docking the same compounds against falcipain-2 [15]. However, we noticed that the 7-chloroquinoline ring of compounds 1 fails to form p-p interactions with the conserved Trp179 due to steric hindrance by residue Phe137 in babesipain-1.…”

Section: Docking Resultssupporting

confidence: 83%

“…Analytical and structural information for Fig. 1 Structures of test compounds, previously reported as micromolar inhibitors of falcipains each compound was found to be in perfect agreement with reported data [15].…”

Section: Synthesis Of Compounds 1-2supporting

confidence: 83%

“…Close inspection of data obtained (Table 1, columns 3 and 7), and comparison with the falcipain inhibitory activities reported in [15] for the same compounds, shows the following:…”

Section: Resultsmentioning

confidence: 69%

“…Although 3 Å seems to be a reasonable distance for a covalent bond between the enzyme and compounds 1, the placement of the rather rigid cinnamoyl group in S2 severely hinders an attack by the catalytic Cys, which may account for the modest inhibitory activity shown by HEDICINS against babesipain-1. Noteworthy, docking of 1c shows that this compound is able to fit into the babesipain-1 binding site, which corroborates its in vitro activity (IC 50 = 27.7 lM), but contrasts with the compound's behavior as a falcipain-2 inhibitor [15]: 1c was previously found to be inactive against falcipain-2 due to the bulky para-isopropyl group blocking its fitting into the Table 4 Important residues lining the binding pockets of babesipain-1 and falcipain-2 Cysteine protease S1 0 S1 S2 S3…”

Section: Docking Resultsmentioning

confidence: 73%

“…1), which were previously reported as micromolar falcipain inhibitors [15]. The interactions of these compounds with babesipain-1 were studied in silico, in order to rationalize in vitro data at the molecular level and guide future design of suitable inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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

Pérez

Antunes

Gonçalves

et al. 2013

J Comput Aided Mol Des

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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.

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Section: Docking Resultssupporting

confidence: 83%

Section: Synthesis Of Compounds 1-2supporting

confidence: 83%

“…Close inspection of data obtained (Table 1, columns 3 and 7), and comparison with the falcipain inhibitory activities reported in [15] for the same compounds, shows the following:…”

Section: Resultsmentioning

confidence: 69%

Section: Docking Resultsmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

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