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

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.