Abstract
Alkaptonuria is an inherited disease that is caused by homogenticate accumulation. Deficiency or mutation in Homogentisate 1,2 dioxygenase gene (chromosome 3q21-q23) leads to production of incorrectly folded or truncated enzyme. Several studies indicated that competitive inhibitors of Homogentisate 1,2 dioxygenase like Nitisinone could be used for Alkaptonuria treatment. Therefore, it is of interest to design better inhibitors of the enzyme. We used subset 3_p.0.5 from Zinc database as the virtual screening library by PyRx software relaying on Lamarckian genetics algorithm. Top 10 hits with more efficient binding affinity were analyzed and hit No#5 and No# 7 was selected for further design. In Lig No#5, we decreased the hydrophobicity by adding oxygen in the hydrophobic tail of the molecule at positions C5 and C10. The new compound of (2Z, 5Z, 8Z)-6,9-Dihydroxy-2-(2-hydroxy-5-oxo-1,3-cyclohexadien-1-yl)-2,5,8-decatrienoic acid satisfied Lipinski rules as well as PhysChem and FafDrugs filters. Moreover, the modified version of Lig No# 7 with the IUPAC name of [2-(Carboxymethyl)-3,5-dihydroxyphenyl] acetic acid satisfies the Lipisnki, FafDrugs and Physchem.
Highlights
Tyrosine (4-hydroxyphenylalanine) pathway is a key pathway
Several genetic disorders are associated with the tyrosine pathway and Alkaptonuria is common among them
It is caused by defect in homogentisate dioxygenase leading to homogentisic acid accumulation [6]
Summary
Tyrosine (4-hydroxyphenylalanine) pathway is a key pathway It is the precursor of several vital chemicals. Several genetic disorders are associated with the tyrosine pathway and Alkaptonuria is common among them. It is caused by defect in homogentisate dioxygenase leading to homogentisic acid accumulation [6]. 3-Cyclopropanecarbonyloxy-2-cyclohexen-1-one reported as a potent non-triketone type inhibitor of 4-hydroxyphenylpyruvate dioxygenase [8]. The carbonyl groups within the identified structure were reported to be crucial in the binding efficiency Both N-acetylcysteine and Cyclopropanecarbonyloxy-2-cyclohexen-1one are Hydroxyphenylpyruvate dioxygenase inhibitors, which by binding to the active site of enzyme and making steric condense, inhibit catalysis in a competitive manner. The most clinical signs of alkaptonuria are related to homogentisic acid accumulation and its polymerization. For decreasing the flexibility of the molecule, we have changed three single bonds to double, one at position C4 and the other at C9 and C20
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