Conformational studies of biologically active natural products : taxol and insect neuropeptides /
The application of 2D NMR spectroscopy and molecular rofilm Inc. modeling to the conformational study of two classes of biologically active compounds possessing high conformational freedom and for which no 3D pharmacophore structure is known is presented. Analogs with unnatural constituents at the 2...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1998.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=733050431&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The application of 2D NMR spectroscopy and molecular rofilm Inc. modeling to the conformational study of two classes of biologically active compounds possessing high conformational freedom and for which no 3D pharmacophore structure is known is presented. Analogs with unnatural constituents at the 2'-position of the anticancer drug tool were synthesized, their biological activity was evaluated, and their conformations were investigated in solvent systems that could mimic different cellular environments. Analogs with no hydrogen bond donors at the 2'- position have conformations that resemble those of taxol in the same media, and show no biological activity. It is therefore proposed that the necessary 2'-hydroxyl functional group is directly involved in hydrogen bonding with microtubules, playing an important role in molecular recognition. Studies on active insect neuropeptide analogs of the allatostatin and kinin families are described in the second section. NMR analysis and molecular modeling on four allatostatin analogs containing turn-promoting unnatural amino acids or peptidomimetic replacements in the [] active core indicate that the consensus secondary structure for this region is a []-turn, characterized by a hydrogen bond between the Leu NH and Asn backbone carbonyl oxygen. Molecular dynamics simulations using continuum and explicit solvation models on the active kinin analog [] NHZ show that the peptide exists as two interconnecting a-turns involving residues 1-4 and 2-5, corroborating previously reported observations on cyclic analogs. The implications of these findings in the development of environmentally safe insect control agents are discussed. The development of new molecular modeling methods is detailed in the last section.Routines for unbiased superposition of large structural ensembles and for the incorporation of chemical shift constraints into molecular modeling simulations are described. The capabilities of software created to implement these methodologies are summarized. |
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| Item Description: | Vita. "Major Subject: Chemistry". |
| Physical Description: | xvi, 273 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 184-195). |