Conformational modeling of neurokinins: Proposed bio-active conformations for different receptor subtypes
Sriniyasan, Rajgopal
This item is only available for download by members of the University of Illinois community. Students, faculty, and staff at the U of I may log in with your NetID and password to view the item. If you are trying to access an Illinois-restricted dissertation or thesis, you can request a copy through your library's Inter-Library Loan office or purchase a copy directly from ProQuest.
Permalink
https://hdl.handle.net/2142/23601
Description
Title
Conformational modeling of neurokinins: Proposed bio-active conformations for different receptor subtypes
Author(s)
Sriniyasan, Rajgopal
Issue Date
1994
Doctoral Committee Chair(s)
Katzenellenbogen, John A.
Department of Study
Chemistry, Organic
Chemistry, Pharmaceutical
Discipline
Chemistry, Organic
Chemistry, Pharmaceutical
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Chemistry, Pharmaceutical
Language
eng
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.
Use this login method if you
don't
have an
@illinois.edu
email address.
(Oops, I do have one)
IDEALS migrated to a new platform on June 23, 2022. If you created
your account prior to this date, you will have to reset your password
using the forgot-password link below.
