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.
Highlights
Tyrosine degradation pathway is one of the key pathways in human physiology, which is associated with several genetic disorders
Tyrosinemia type II is the results of missense mutation in tyrosine trans aminase, which is the first enzyme involved in the degradation pathway [3]
Tyrosinemia type III is caused by pHydroxyphenyl pyruvate accumulation in the body that is the result of genetical defect in the gene of p-Hydroxyphenyl pyruvate dioxygenase [4]
Summary
Tyrosine degradation pathway is one of the key pathways in human physiology, which is associated with several genetic disorders. Several enzymes are engaged in the degradation pathway of tyrosine which any defect of pathogenic mutation in the enzyme genes would cause serious clinical signs. Tyrosinemia type I is the result of fumaryl acetoacetase defection and 4-fumaryl acetoacetate accumulation It is a rare autosomal recessive genetic metabolic disorder and its symptoms appear in the first month of the life including failure to gain weight and grow at the expected rate, fever, diarrhea, vomiting and hepatomegaly [5]. Nitisinone is a competitive inhibitor of 4-hydroxyphenylpiruvic acid dioxygenase It decreases the cellular level of Homogentisic acid, an intermediate chemical and precursor of fumarylacetoacetate. For better treatment of tyrosinemia type I it is essential to target a more specific enzyme engaged in fumarylacecoacetate formation For gaining this purpose, we have tried to design specific chemicals that target 4maleylacetoacetate isomerase, which is directly responsible for fumarylacecoacetate production. Virtual screening and rational drug design techniques was used
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