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Title |
Competitive rational inhibitor design to 4-maleylaceto-acetate isomerase
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Authors |
Narges Zolfaghari1,*
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Affiliation |
1National institute of genetic engineering and biotechnology, Tehran, Iran;
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Article Type |
Hypothesis
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Date |
Received April 27, 2017; Accepted May 1, 2017; Published May 31, 2017
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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.
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Keywords |
Tyrosinemia type I, Nitisinone, 4- maleylacetoacetate isomerase, rational drug design
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Citation |
Zolfaghari, Bioinformation 13(5): 140-143 (2017)
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Edited by |
P Kangueane
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ISSN |
0973-2063
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Publisher |
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License |
This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.
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