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Topographical design of the message domain pharmacophore of the delta opioid agonists using designer amino acids and design of non-peptide ligand for opioid receptors.A series of highly constrained tyrosine derivatives, 2',6'-dimethyl- β-methyltyrosines (TMTs), was designed and asymmetrically synthesized. Incorporation of the TMT isomers into peptide agonists of δ opioid receptors provide analogues that are highly potent and selectively for δ opioid receptors and have revealed the stereochemical requirements for recognizing opioid δ receptors. Moreover, the combination of conformational studies and pharmacological studies of the peptide analogues provided for the first time the stereochemical requirements for specifically recognizing opioid δ receptor subtypes. The biological active conformation of a highly selective and potent δ opioid agonist, ((2S,3R)-TMT¹) DPDPE, was obtained by NMR studies and computer-assisted modeling. This conformation was then further used for designing novel non-peptide opioid ligands. Thus, this study is another achievement of topographical design of peptide hormones and neurotransmitters. Practically, the results of this study can be used to develop more biological stable pharmaceuticals as strong pain reliever without causing side effects such as physical dependence, respiratory depression, etc.
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A semantics-based methodology for integrated distributed database design: Toward combined logical and fragmentation design and design automation.The many advantages of Distributed Database (DDB) systems can only be achieved through proper DDB designs. Since designing a DDB is very difficult and expert designers are relatively few in number, "good" DDB design methodologies and associated computer-aided design tools are needed to help designers cope with design complexity and improve their productivity. Unfortunately, previous DDB design research focused on solving subproblems of data distribution design in isolation. As a result, past research on a general DDB design methodology offered only methodological frameworks that, at best, aggregate a set of non-integrated design techniques. The conventional separation of logical design from fragmentation design is problematic, but has not been fully analyzed. This dissertation presents the SEER-DTS methodology developed for the purposes of overcoming the methodological inadequacies of conventional design methodologies, resolving the DDB design problem in an integrated manner and facilitating design automation. It is based on a static semantic data model, SEER (Synthesized Extended Entity-Relationship Model) and a dynamic data model, DTS (Distributed Transaction Scheme), which together provide complete and consistent modeling mechanisms for acquiring/representing DDB design inputs and facilitating DDB schema design. In this methodology, requirement/distribution analysis and conceptual design are integrated and logical and fragmentation designs are combined. "Semantics-based" design techniques have been developed to allow for end-user design specifications and seamless design schema transformations, thereby simplifying design tasks. Towards our ultimate goal of design automation, an architectural framework for a computer-aided DDB design system, Auto-DDB, was formulated and the system was prototyped. As part of the developmental effort, a real-world DDB design case study was conducted to verify the applicability of the SEER-DTS methodology in a manual design mode. The results of a laboratory experiment showed that the SEER-DTS methodology produced better design outcomes (in terms of design effectiveness and efficiency) than a Conventional Best methodology performed by non-expert designers in an automated design mode. However, no statistically significant difference was found in user-perceived ease of use.
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Design and synthesis of topographically constrained amino acids, and bioactive peptides for studies of ligand-receptor interaction, and for de novo design of delta-opioid selective non-peptide mimetics as potential therapeuticsTopographical constraint is the most powerful approach for the design of bioactive peptides to explore the bioactive conformation of crucial side-chain pharmacophores of amino acid residues in peptide-receptor recognition and signal transduction. Novel topographically constrained amino acids β-isopropylphenylalanine and 2',6'-dimethyl-2,3-methanophenylalanine have been designed and synthesized. Incorporation of the four optically pure β-isopropylphenylalanine stereoisomers into deltorphin I produced four peptide analogues of [β-iPrPhe]Deltorphin I with differentiated bioactivities. The most potent and selective analogue, [(2S,3R)-β-iPrPhe]Deltorphin I showed an IC₅₀ nM binding affinity, and a 29000 fold selectivity for the δ-opioid receptor over the μ opioid receptor. Combined molecular modeling and NMR studies indicated that the (2S,3R)-β-iPrPhe³ residue in the analogue favors the trans rotamer, and can induce the linear peptide to form a low-energy folded conformation which was proposed as the bioactive conformation for the δ-opioid receptor. Coupling four optically pure, conformationally constrained β-methyl-2',6'-dimethyltyrosine (TMT) with L-Tic formed four dipeptide analogues of TMT-L-Tic. The most potent and selective analogue, (2S,3R)-TMT-L-Tic showed 9 nM binding affinity and 4000 fold selectivity to the δ vs μ opioid receptor. The lowest-energy conformation of (2S,3R)-TMT-L-Tic was suggested to be the bioactive one in which TMT side chain is trans and Tic side chain is in a gauche (+) conformation. Bicyclic oxytocin antagonist [dPen¹, cyclo(Glu⁴ Lys⁸)]OT (BC-OT) (pA₂ = 8.10) is an excellent template to examine further topographical ideas. Substitution of Tyr² with the topographically constrained para-methoxy-β-methyl-2',6'-dimethyltyrosine (p-MeOTMT) amino acids produced two very potent antagonists [(2S,3S)-p-MeOTMT²]BC-OT (pA₂ = 8.26) and [(2R,3R)-p-MeOTMT²]BC-OT(pA₂ = 7.80), and two inactive analogues [(2S,3R)-p-MeOTMT²]BC-OT and [(2R,3S)-p-MeOTMT²]BC-OT. These interesting results can be attributed to the biased side-chain conformation, gauche(+) and gauche(-) in (2S,3S)-p-MeOTMT and (2R,3R)-p-MeOTMT respectively, and trans in both (2S,3R)-p-MeOTMT and (2R,3S)-p-MeOTMT residues. Rational design of non-peptide mimetics from peptide leads is still elusive. Based on the δ-opioid selective lead [(2S,3R)-TMT¹]DPDPE and SAR of δ-opioid selective ligands, the first generation of non-peptide mimetics have been designed and synthesized. The new lead SL-3111 showed binding affinity IC₅₀ = 8 nM, and over 2000 fold selectivity for the δ-opioid receptor over the μ receptor.
