Dataset Information

Molecular docking analysis of nitisinone with homogentisate 1,2 dioxygenase.

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.

SUBMITTER: Zolfaghari N

PROVIDER: S-EPMC5498778 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Molecular docking analysis of nitisinone with homogentisate 1,2 dioxygenase.

Zolfaghari Narges N

Bioinformation 20170531 5

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 virtu ...[more]

PMID: 28690378

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Project description:Alkaptonuria (AKU) is a rare inborn error of metabolism caused by a defective homogentisate 1,2-dioxygenase (HGD), an enzyme involved in the tyrosine degradation pathway. Loss of HGD function leads to the accumulation of homogentisic acid (HGA) in connective body tissues in a process called ochronosis, which results on the long term in an early-onset and severe osteoarthropathy. HGD's quaternary structure is known to be easily disrupted by missense mutations, which makes them an interesting target for novel treatment strategies that aim to rescue enzyme activity. However, only prediction models are available providing information on a structural basis. Therefore, an E. coli based whole-cell screening was developed to evaluate HGD missense variants in 96-well microtiter plates. The screening principle is based on HGD's ability to convert the oxidation sensitive HGA into maleylacetoacetate. More precisely, catalytic activity could be deduced from pyomelanin absorbance measurements, derived from the auto-oxidation of remaining HGA. Optimized screening conditions comprised several E. coli expression strains, varied expression temperatures and varied substrate concentrations. In addition, plate uniformity, signal variability and spatial uniformity were investigated and optimized. Finally, eight HGD missense variants were generated via site-directed mutagenesis and evaluated with the developed high-throughput screening (HTS) assay. For the HTS assay, quality parameters passed the minimum acceptance criterion for Z' values > 0.4 and single window values > 2. We found that activity percentages versus wildtype HGD were 70.37 ± 3.08% (for M368V), 68.78 ± 6.40% (for E42A), 58.15 ± 1.16% (for A122V), 69.07 ± 2.26% (for Y62C), 35.26 ± 1.90% (for G161R), 35.86 ± 1.14% (for P230S), 23.43 ± 4.63% (for G115R) and 19.57 ± 11.00% (for G361R). To conclude, a robust, simple, and cost-effective HTS system was developed to reliably evaluate and distinguish human HGD missense variants by their HGA consumption ability. This HGA quantification assay may lay the foundation for the development of novel treatment strategies for missense variants in AKU.

Dataset Information

Molecular docking analysis of nitisinone with homogentisate 1,2 dioxygenase.

Publications

Molecular docking analysis of nitisinone with homogentisate 1,2 dioxygenase.

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