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Computational analysis of the cathepsin B inhibitors activities through LR-MMPBSA binding affinity calculation based on docked complex.

ABSTRACT: Cathepsin B, a ubiquitous lysosomal cysteine protease, is involved in many biological processes related to several human diseases. Inhibitors targeting the enzyme have been investigated as possible diseases treatments. A set of 37 compounds were recently found active in a high throughput screening assay to inhibit the catalytic activity of Cathepsin B, with chemical structures and biological test results available to the public in the PubChem BioAssay Database (AID 820). In this study, we compare these experimental activities to the results of theoretical predictions from binding affinity calculation with a LR-MM-PNSA approach based on docked complexes. Strong correlations (r(2) = 0.919 and q(2) = 0.887 for the best) are observed between the theoretical predictions and experimental biological activity. The models are cross-validated by four independent predictive experiments with randomly split compounds into training and test sets. Our results also show that the results based on protein dimer show better correlations with experimental activity when compared to results based on monomer in the in silico calculations.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC2735608 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Computational analysis of the cathepsin B inhibitors activities through LR-MMPBSA binding affinity calculation based on docked complex.

Zhou Zhigang Z Wang Yanli Y Bryant Stephen H SH

Journal of computational chemistry 20091101 14

Cathepsin B, a ubiquitous lysosomal cysteine protease, is involved in many biological processes related to several human diseases. Inhibitors targeting the enzyme have been investigated as possible diseases treatments. A set of 37 compounds were recently found active in a high throughput screening assay to inhibit the catalytic activity of Cathepsin B, with chemical structures and biological test results available to the public in the PubChem BioAssay Database (AID 820). In this study, we compar ...[more]

PMID: 19242965

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Project description:BACKGROUND:Increased reports of human infections have led fasciolosis, a widespread disease of cattle and sheep caused by the liver flukes Fasciola hepatica and Fasciola gigantica, to be considered an emerging zoonotic disease. Chemotherapy is the main control measure available, and triclabendazole is the preferred drug since is effective against both juvenile and mature parasites. However, resistance to triclabendazole has been reported in several countries urging the search of new chemical entities and target molecules to control fluke infections. METHODOLOGY/PRINCIPLE FINDINGS:We searched a library of forty flavonoid derivatives for inhibitors of key stage specific Fasciola hepatica cysteine proteases (FhCL3 and FhCL1). Chalcones substituted with phenyl and naphtyl groups emerged as good cathepsin L inhibitors, interacting more frequently with two putative binding sites within the active site cleft of the enzymes. One of the compounds, C34, tightly bounds to juvenile specific FhCL3 with an IC50 of 5.6 ?M. We demonstrated that C34 is a slow-reversible inhibitor that interacts with the Cys-His catalytic dyad and key S2 and S3 pocket residues, determinants of the substrate specificity of this family of cysteine proteases. Interestingly, C34 induces a reduction in NEJ ability to migrate through the gut wall and a loss of motility phenotype that leads to NEJ death within a week in vitro, while it is not cytotoxic to bovine cells. CONCLUSIONS/SIGNIFICANCE:Up to date there are no reports of in vitro screening for non-peptidic inhibitors of Fasciola hepatica cathepsins, while in general these are considered as the best strategy for in vivo inhibition. We have identified chalcones as novel inhibitors of the two main Cathepsins secreted by juvenile and adult liver flukes. Interestingly, one compound (C34) is highly active towards the juvenile enzyme reducing larval ability to penetrate the gut wall and decreasing NEJ´s viability in vitro. These findings open new avenues for the development of novel agents to control fluke infection and possibly other helminthic diseases.

Dataset Information

Computational analysis of the cathepsin B inhibitors activities through LR-MMPBSA binding affinity calculation based on docked complex.

Publications

Computational analysis of the cathepsin B inhibitors activities through LR-MMPBSA binding affinity calculation based on docked complex.

Similar Datasets

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