Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling

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dc.contributor.advisorJackson, Graham Ellisen_ZA
dc.contributor.authorMaliekal, James Cen_ZA
dc.date.accessioned2015-05-13T14:24:24Z
dc.date.available2015-05-13T14:24:24Z
dc.date.issued1999en_ZA
dc.descriptionBibliographical references (pages 125-132)en_ZA
dc.description.abstractGonadotropin releasing hormone (GnRH) is a decapeptide with blocked amino and carboxy termini and plays a central role in reproduction. Mammalian GnRH has a positively charged Arg8 residue and binds to the mammalian receptor with high affinity. However, the neutral analog Cln8GnRH has very low affinity. The affinity is restored when the Gly6 is replaced by the achiral D-Trp6, or the Gly6 and Leu7 are modified to form a 6,7 y-lactarn. His5Trp7Tyr8GnRH also shows reasonably high affinity. A comprehensive conformational search was carried out using Nuclear Magnetic Resonance spectroscopy and Simulated annealing to identify the bio-active conformations and to explain the different binding affinities of these peptide analogs. The interproton distances and backbone torsion angles obtained from the NMR data were used to constrain the peptides during the simulated annealing. A large number of structures were generated for each peptide and their conformations analyzed. All live peptides showed some degree of flexibility of conformation, mainly in the terminal domains. The four high affinity analogs all had similar backbones with a β type bend around the Glys residue and the two termini in proximity. The Arg8 in GnRH was involved in several hydrogen bonds that stabilized the folded conformation. In contrast, the inactive Gln8GnRH had a markedly different conformation, with the termini pointing away from each other. The lowest energy structures identified from the simulated annealing were used in subsequent receptor-ligand docking studies. All the high affinity analogs were found to fit neatly into the binding pocket. Arg8 of GnRH formed several H-bonds with residues on the receptor. However, Gln8GnRH showed a poor fit and considerable repulsion between ligand and receptor was evident. The Gln8 did not form H-bonds with the receptor. The calculated binding energies were consistent with the relative binding potencies observed for all five analogs studied.en_ZA
dc.identifier.apacitationMaliekal, J. C. (1999). <i>Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/12802en_ZA
dc.identifier.chicagocitationMaliekal, James C. <i>"Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 1999. http://hdl.handle.net/11427/12802en_ZA
dc.identifier.citationMaliekal, J. 1999. Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Maliekal, James C AB - Gonadotropin releasing hormone (GnRH) is a decapeptide with blocked amino and carboxy termini and plays a central role in reproduction. Mammalian GnRH has a positively charged Arg8 residue and binds to the mammalian receptor with high affinity. However, the neutral analog Cln8GnRH has very low affinity. The affinity is restored when the Gly6 is replaced by the achiral D-Trp6, or the Gly6 and Leu7 are modified to form a 6,7 y-lactarn. His5Trp7Tyr8GnRH also shows reasonably high affinity. A comprehensive conformational search was carried out using Nuclear Magnetic Resonance spectroscopy and Simulated annealing to identify the bio-active conformations and to explain the different binding affinities of these peptide analogs. The interproton distances and backbone torsion angles obtained from the NMR data were used to constrain the peptides during the simulated annealing. A large number of structures were generated for each peptide and their conformations analyzed. All live peptides showed some degree of &#64258;exibility of conformation, mainly in the terminal domains. The four high affinity analogs all had similar backbones with a &#946; type bend around the Glys residue and the two termini in proximity. The Arg8 in GnRH was involved in several hydrogen bonds that stabilized the folded conformation. In contrast, the inactive Gln8GnRH had a markedly different conformation, with the termini pointing away from each other. The lowest energy structures identified from the simulated annealing were used in subsequent receptor-ligand docking studies. All the high affinity analogs were found to fit neatly into the binding pocket. Arg8 of GnRH formed several H-bonds with residues on the receptor. However, Gln8GnRH showed a poor fit and considerable repulsion between ligand and receptor was evident. The Gln8 did not form H-bonds with the receptor. The calculated binding energies were consistent with the relative binding potencies observed for all &#64257;ve analogs studied. DA - 1999 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1999 T1 - Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling TI - Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling UR - http://hdl.handle.net/11427/12802 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/12802
dc.identifier.vancouvercitationMaliekal JC. Conformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modelling. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 1999 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/12802en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.titleConformational and docking studies of Gonadotropin releasing hormone and its analogsby NMR spectroscopy and molecular modellingen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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