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Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay.

Wiggers HJ, Rocha JR, Fernandes WB, Sesti-Costa R, Carneiro ZA, Cheleski J, da Silva AB, Juliano L, Cezari MH, Silva JS, McKerrow JH, Montanari CA - PLoS Negl Trop Dis (2013)

Bottom Line: Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation.Two compounds were found to have trypanocidal activity.The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.

ABSTRACT
A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization.

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2D structural representation of (A) K11777 and (B) WRR-483 inhibitors.
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pntd-0002370-g001: 2D structural representation of (A) K11777 and (B) WRR-483 inhibitors.

Mentions: A promising molecular class acting with antiparasitic activity can be found in vinyl sulfones. In pre-clinical trials, the inhibitor K11777 (Figure 1A) has been shown to be non-mutagenic, well tolerated, to have an acceptable pharmacokinetic profile and demonstrated efficacy in models of acute and chronic Chagas disease both in mice and dogs [13]. Additional studies of vinyl sulfone compounds have led to the identification of an arginine variant of K11777, named WRR-483 (Figure 1B) with remarkable biological properties [14].


Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay.

Wiggers HJ, Rocha JR, Fernandes WB, Sesti-Costa R, Carneiro ZA, Cheleski J, da Silva AB, Juliano L, Cezari MH, Silva JS, McKerrow JH, Montanari CA - PLoS Negl Trop Dis (2013)

2D structural representation of (A) K11777 and (B) WRR-483 inhibitors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750009&req=5

pntd-0002370-g001: 2D structural representation of (A) K11777 and (B) WRR-483 inhibitors.
Mentions: A promising molecular class acting with antiparasitic activity can be found in vinyl sulfones. In pre-clinical trials, the inhibitor K11777 (Figure 1A) has been shown to be non-mutagenic, well tolerated, to have an acceptable pharmacokinetic profile and demonstrated efficacy in models of acute and chronic Chagas disease both in mice and dogs [13]. Additional studies of vinyl sulfone compounds have led to the identification of an arginine variant of K11777, named WRR-483 (Figure 1B) with remarkable biological properties [14].

Bottom Line: Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation.Two compounds were found to have trypanocidal activity.The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.

ABSTRACT
A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization.

Show MeSH
Related in: MedlinePlus