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Conformational analysis of flexible molecules: An investigation and evaluation of NMR-based modeling approaches

Pieter Hendrickx UGent (2009)
abstract
This manuscript describes the results of the NMR investigation of several possible peptide and non-peptidic molecules that may constitute drug leads. For this purpose, classical and modern molecular modeling approaches based on experimental NMR data were followed to obtain insight in these molecules’ three dimensional structure. Conformational analyses of a variety of five membered ring systems, i.e. furanoses, proline scaffolds and thymidine-kinase inhibitors, were performed. A user-friendly, MATLAB-based GUI has been implemented to facilitate the classical pseudorotation analysis procedure (PRA) for such compounds. Furthermore, time-averaged restrained molecular dynamics simulations were introduced in the current research as a valuable alternative conformational analysis approach. This latter approach was thoroughly tested on a set of six furanose compounds and used afterward to calculate the conformation space accessible to several proline scaffolds and thymidine-kinase inhibitors. Together with PRA, this secondary modeling approach allows a more accurate interpretation of a five membered ring conformation. A similar approach was followed for the conformational analysis of a single dipeptide containing a -cyclohexane amino acid residue. First, a combination of scalar coupling and nOe data were used to analyze the relative topology of the stereogenic carbon centers of this molecule, as these were unclear from the synthesis scheme followed. Additional, a second MATLAB-based GUI has been implemented for the conformational investigation of this type of molecules using the PRA approach. This enables the determination of the stability of both cyclohexane chair conformations. Furthermore, time-averaged restrained molecular dynamics simulations were conducted showing additional twist-boat conformations. This observation could be assigned to the high potential energy barriersthat need to be crossed to invert a cyclohexane chair. Next to the investigation of these small rings, a set of four dermorphin analogs and two somatostatin analogs were studied. Their conformation was assessed both using the classical simulated annealing approach and time-averaged restrained molecular dynamics simulations. Both approaches are based on experimental measured proton-proton distances, which were measured using a 2D ROESY pulse scheme containing an off-resonance spin-lock. The use of the tar-MD approach showed a clear improvement over the classical SA approach when considering the dermorphin analogs. This can be directly linked to the rationale behind both techniques. Tar-MD allows for local and to some extent global flexibility in the system studied whereas SA was eveloped to determine conformations of rigid systems. A clear difference in conformational behavior was established due to the -methylation of the phenylalanine residue. Unfortunately, no structure-activity relationship could be readily proposed based upon these results. Two somatostatin analogs were studied in two solvents using both analysis techniques. Using the SA approach, only the investigation of one analog resulted in a nicely defined conformation in d6-DMSO. Additionally, a concentration study in d3-acetonitrile showed the association of both analogs into a dimeric form. Possible approaches to determine this dimeric conformation are iterated and preliminary results are reported. In addition, Appendix A holds the manuscripts of several additional research projects which have been published in international peer-reviewed journals or are being prepared to be submitted.
Please use this url to cite or link to this publication:
author
promoter
UGent
organization
alternative title
Conformational analysis of flexible molecules
year
type
dissertation (monograph)
subject
keyword
NMR, conformational analysis, proline, somatostatin, dermorphin, thymidine kinase
pages
277 pages
publisher
N/A
place of publication
Gent
defense location
Het Pand - Zaal Rector Blancquaert
defense date
2009-06-16 14:00
language
English
UGent publication?
yes
classification
D1
id
788470
handle
http://hdl.handle.net/1854/LU-788470
date created
2009-11-24 11:58:36
date last changed
2009-11-25 11:02:46
@phdthesis{788470,
  abstract     = {This manuscript describes the results of the NMR investigation of several possible peptide and non-peptidic molecules that may constitute drug leads. For this purpose, classical and modern molecular modeling approaches based on experimental NMR data were followed to obtain insight in these molecules{\textquoteright} three dimensional structure. Conformational analyses of a variety of five membered ring systems, i.e. furanoses,
proline scaffolds and thymidine-kinase inhibitors, were performed. A user-friendly, MATLAB-based GUI has been implemented to facilitate the classical pseudorotation analysis procedure (PRA) for such compounds. Furthermore, time-averaged restrained molecular dynamics simulations were introduced in the current research as a valuable alternative conformational analysis approach. This
latter approach was thoroughly tested on a set of six furanose compounds and used afterward to calculate the conformation space accessible to several proline scaffolds and thymidine-kinase inhibitors. Together with PRA, this secondary modeling approach allows a more accurate interpretation of a five membered ring conformation.
A similar approach was followed for the conformational analysis of a single dipeptide containing a \unmatched{000c}-cyclohexane amino acid residue. First, a combination of scalar coupling and nOe data were used to analyze the relative topology of the stereogenic carbon centers of this molecule, as these were unclear from the synthesis scheme followed. Additional, a second MATLAB-based GUI has been implemented for the conformational investigation of this type of molecules using the PRA approach. This enables the determination of the stability of both cyclohexane chair conformations. Furthermore, time-averaged restrained molecular dynamics simulations were conducted showing additional twist-boat conformations. This observation could be assigned to the high potential energy barriersthat need to be crossed to invert a cyclohexane chair.
Next to the investigation of these small rings, a set of four dermorphin analogs and two somatostatin analogs were studied. Their conformation was assessed both using the classical simulated annealing approach and time-averaged restrained molecular dynamics simulations. Both approaches are based on experimental measured proton-proton distances, which were measured using a 2D ROESY pulse scheme containing an off-resonance spin-lock. The use of the tar-MD approach showed a clear improvement over the classical SA approach when considering the dermorphin analogs. This can be directly linked to the rationale behind both techniques. Tar-MD allows for local and to some extent global flexibility in the system studied whereas SA was eveloped
to determine conformations of rigid systems. A clear difference in conformational behavior was established due to the \unmatched{000b}-methylation of the phenylalanine residue. Unfortunately, no structure-activity relationship could be readily proposed based upon these results.
Two somatostatin analogs were studied in two solvents using both analysis techniques. Using the SA approach, only the investigation of one analog resulted in a nicely defined conformation in d6-DMSO. Additionally, a concentration study in d3-acetonitrile showed the association of both analogs into a dimeric form. Possible approaches to determine this dimeric conformation are iterated and preliminary results are reported. In addition, Appendix A holds the manuscripts of several additional research projects which have been published in international peer-reviewed journals or are being prepared to be submitted.},
  author       = {Hendrickx, Pieter},
  keyword      = {NMR,conformational analysis,proline,somatostatin,dermorphin,thymidine kinase},
  language     = {eng},
  pages        = {277},
  publisher    = {N/A},
  school       = {Ghent University},
  title        = {Conformational analysis of flexible molecules: An investigation and evaluation of NMR-based modeling approaches},
  year         = {2009},
}

Chicago
Hendrickx, Pieter. 2009. “Conformational Analysis of Flexible Molecules: An Investigation and Evaluation of NMR-based Modeling Approaches”. Gent: N/A.
APA
Hendrickx, P. (2009). Conformational analysis of flexible molecules: An investigation and evaluation of NMR-based modeling approaches. N/A, Gent.
Vancouver
1.
Hendrickx P. Conformational analysis of flexible molecules: An investigation and evaluation of NMR-based modeling approaches. [Gent]: N/A; 2009.
MLA
Hendrickx, Pieter. “Conformational Analysis of Flexible Molecules: An Investigation and Evaluation of NMR-based Modeling Approaches.” 2009 : n. pag. Print.