Computational Study of Human Tyrosine Hydroxylase Mutants to Uphold [4-(Propan-2-yl) Phenyl]Carbamic Acid as a Potential Inhibitor

Author(s): Muhammad S. Nawaz , Zahida Parveen , Liyong Wang , Sajid Rashid , Muhammad Q. Fatmi , Mohammad A. Kamal .

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 13 , Issue 7 , 2014

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Abstract:

Neurodegenerative diseases that afflict nervous system are characterized by progressive nervous system dysfunction and associated with the one-set of many diseases like Segawa’s syndrome (recessive form), autosomal recessive L-dopa-responsive dystonia, L-dopa non-responsive dystonia or progressive early-onset encephalopathy and recessive L-dopa-responsive parkinsonism. It has been reported that a number of mutations in coding regions, splice sites and promoter regions of tyrosine hydroxylase (TH) are associated with many such diseases. TH is responsible for catalyzing the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine. This reaction is considered as rate-limiting step in the biosynthesis of catecholamines, dopamine, norepinephrine and epinephrine, which has made TH an important target for drug development. In our previous study using comparative molecular docking approach, it was concluded that [4- (Propan-2-yl) Phenyl]Carbamic acid (PPCA) may serve as a potential inhibitor. By further extending, our focus is to determine the binding affinities of PPCA and mutated TH. 3D structures of mutated TH were predicted and subjected to molecular docking studies. PPCA was found to bind in the deep narrow groove lined with polar and aromatic amino acids in 14 out of 17 mutants under study (R202H, L205P, H215Y, G216S, T245P, F278P, T283M, R297W, R306H, C328F, A345V, L356M, T368M, Q381K, P461L, T463M and D467G). Our results corroborate efficient binding of PPCA with normal and mutated TH, indicating that PPCA might be a strong therapeutic candidate for the management of Parkinson’s disease and other related disorders. It may be a valuable target for evaluation in preclinical models.

Keywords: Docking, mutation, bioinformatics, Parkinson’s disease, tyrosine hydroxylase.

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Article Details

VOLUME: 13
ISSUE: 7
Year: 2014
Page: [1169 - 1174]
Pages: 6
DOI: 10.2174/1871527313666140917111905
Price: $58

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