STRUCTURE AND LIGAND BASED DRUG DESIGNING OF AMINO ACID HYDROXYLASE ENZYMES INVOLVED IN NEURODEGENERATION

Abstract

The aromatic amino acid hydroxylases represent a family of structurally and functionally closely related enzymes like phenylalanine hydroxylases, tyrosine hydroxylases and tryptophan hydroxylases. All the enzymes catalyze key steps in important metabolic pathways by utilizing a cofactor known as tetrahydrobiopterin. The purpose of the present study is to undertake a molecular docking study for various analogues of the cofactor on these amino acid hydroxylases using GLIDE application of Maestro (a molecular modeling module of Schrodinger software) and to develop a pharmacophore model for the best screened compounds using PHASE application of Maestro (a molecular modeling module of Schrodinger software). The intermolecular hydrogen bonding interaction of the best-fit ligands are found to be associated with Arg270, Glu280, Thr278, Pro279, Gly346, Ser349, Glu353, Val379 and Fe425 amino acid residue at the phenylalanine hydroxylase receptor active site. Among all the observed interactions with similar binding pattern, ligand 6-(1,4-Dihydroxy-2-methyl-butyl)-2-methyl-7,8-dihydro-3H-pteridin-4-one (3 (f)) showed higher affinity with a glide score of -9.3. For tryptophan hydroxylase receptor active site, interactions are found to be associated with Tyr125, Leu236, Thr265, Pro266, Glu317, Gly333, Ser336, Ser337, Glu340, Thr367 and Thr368 and ligand 2,7-Diamino-6-(4-amino-1,2-dihydroxy-butyl)-7-hydroxy-7,8-dihydro-3H-pteridin-4-one (22 (f)) showed higher affinity with a glide score of -10.1. In addition, pharmacophore mapping studies were undertaken for 24 best screened compounds. Two pharmacophore models were developed, a pharmacophore with 2 H bond donors and 2 H bond acceptors and another with 2 H bond donors, 1 H bond acceptor and 1 aromatic ring. The pharmacophore hypotheses yielded a statistically significant 3-D QSAR model with correlation factors of 0.85 and 0.73 respectively for training and test set compounds. Also, the docking studies performed on mutant phenylalanine hydroxylase shows the therapeutic applications of these cofactor analogues.