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Title:Conformational modeling of neurokinins: Proposed bio-active conformations for different receptor subtypes
Author(s):Sriniyasan, Rajgopal
Doctoral Committee Chair(s):Katzenellenbogen, John A.
Department / Program:Chemistry, Organic
Chemistry, Pharmaceutical
Discipline:Chemistry, Organic
Chemistry, Pharmaceutical
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Chemistry, Pharmaceutical
Abstract:The conformations of selective analogues of neurokinins, which share a common C-terminal sequence of Phe-X-Val-Gly-Leu-Met-NH$\sb2$ (where X may be Phe or Val), have been analyzed using Monte Carlo (MC) and high temperature molecular dynamics (MD) techniques. A qualitative model for binding at the different neurokinin receptor sites was generated, based on known conformational preferences of various amino acids, independent of the computations.The conformations generated by MC and MD techniques have been analyzed using structure-activity data as well as solution NMR and CD data, where available. Based on the analyses it is proposed that the biologically relevant conformation for NK-1 receptor sites involves a type I beta turn involving residues Gly-Leu, a type II beta turn involving residues Val-Leu for NK-3 receptor sites, while in NK-2 receptor sites the Gly residue adopts extended conformations. The relationship between the qualitative modeling and the quantitative modeling is discussed. Our model for the NK-1 binding site is different from other proposed models and is supported by more recent experimental studies. The conformation of peptidic and non-peptidic antagonists of NK-1 receptor sites have also been analyzed. These computations have been used to propose a model for agonist vs. antagonist activity at NK-1 receptor sites.
Issue Date:1994
Rights Information:Copyright 1994 Sriniyasan, Rajgopal
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9512559
OCLC Identifier:(UMI)AAI9512559

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