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Competitive rational inhibitor design to 4-maleylaceto-acetate isomerase.

ABSTRACT: Tyrosinemia type I is the result of genetic disorder in fomaryl acetoacetase gene that leads to 4-fumaryl acetoacetate accumulation. The current treatment for tyrosinemia type I is nitisinone that inhibits 4-hydroxyphenyl pyruvic dioxygenase in competitive manner. In the present study, we have designed two theoretical chemicals, which could inhibit the direct enzyme responsible for fumarylacetoacetate formation. Subset 2_p.0.5 from Zinc database was screened by PyRx software using a Lamarckian genetic algorithm as the scoring function for docking. Top nine successive hits were selected for further pharmacological analysis and finally the new designed ligands RD6-2 (3Z)- 1,3-Butadiene-1,1,2,4-tetrol and RD-7-1 ((Z)-3-[4-Hydroxy-1-(hydroxymethyl)cyclohexyl]-2-propene-1,2-diol could pass PhysChem, FAFDrugs and AdmetSAR filter. The designed ligands were non-substrate and non-inhibitor of CYP450 and nontoxic in AMES test. LD50 of RD-6-2 was 793mg/kg with the toxicity class of four and The LD50 of RD-7-1 was calculated as 5000mg/kg within the toxicity class of five. The designed molecules are introduced as the new theoretical small molecules, which can theoretically inhibit 4- maleylacetoacetate isomerase in a competitive manner.

SUBMITTER: Zolfaghari N

PROVIDER: S-EPMC5498779 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Competitive rational inhibitor design to 4-maleylaceto-acetate isomerase.

Zolfaghari Narges N

Bioinformation 20170531 5

Tyrosinemia type I is the result of genetic disorder in fomaryl acetoacetase gene that leads to 4-fumaryl acetoacetate accumulation. The current treatment for tyrosinemia type I is nitisinone that inhibits 4-hydroxyphenyl pyruvic dioxygenase in competitive manner. In the present study, we have designed two theoretical chemicals, which could inhibit the direct enzyme responsible for fumarylacetoacetate formation. Subset 2_p.0.5 from Zinc database was screened by PyRx software using a Lamarckian g ...[more]

PMID: 28690379

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Project description:The ubiquitin-proteasome system is an essential regulator of many cellular processes including controlling protein homeostasis. The degradation of proteins by the multi-subunit proteasome complex is tightly regulated through a series of checkpoints, amongst which are a set of deubiquitinating proteases (DUBs). The proteasome-associated DUBs, UCH-L5 (Ubiquitin carboxyl-terminal hydrolase isozyme L5) and USP14 (Ubiquitin-specific protease 14), and the integral-DUB in the proteasome, Rpn11, is known to regulate proteasomal degradation by deubiquitination of distinct substrates. Although selective inhibitors for USP14 and Rpn11 have been recently developed, there are no known inhibitors that selectively bind to UCH-L5. The X-ray structure of the Ubiquitin (Ub) bound to UCH-L5 shows a β-sheet hairpin in Ub that contains a crucial hydrophobic patch involved in the interaction with UCH-L5. Herein, we designed and developed both a Ub sequence-based linear- and cyclic- β-sheet hairpin peptide that was found to preferably inhibit UCH-L5. We show that these peptides have low micromolar IC50 values and the cyclic peptide competes with the activity-based UbVME (Ubiquitin-Vinyl-Methyl-Ester) probe for UCH-L5, binding in a concentration-dependent manner. We further establish the selectivity profile of the cyclic peptide for UCH-L5 compared to other members of the UCH-DUB family and other cysteine DUBs in cell lysate. Furthermore, the cyclic peptide infiltrated cells resulting in the accumulation of polyUb chains, and was found to be non-toxic at the concentrations used here. Taken together, our data suggest that the cyclic peptide permeates the cell membrane, inhibits UCH-L5 by possibly blocking its deubiquitinating function, and contributes to the accumulation of polyubiquitinated substrates. The implications of inhibiting UCH-L5 in the context of the 26S proteasome render it an attractive candidate for further development as a potential selective inhibitor for therapeutic purposes.

Dataset Information

Competitive rational inhibitor design to 4-maleylaceto-acetate isomerase.

Publications

Competitive rational inhibitor design to 4-maleylaceto-acetate isomerase.

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