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Dissertation Information for Pahk Thepchatri

NAME:
- Pahk Thepchatri

DEGREE:
- Ph.D.

DISCIPLINE:
- Chemistry

SCHOOL:
- Emory University (USA) (2006)

ADVISORS:
- Dennis C. Liotta

COMMITTEE MEMBERS:
- Fred M. Menger
- James T. Kindt

MPACT Status: Fully Complete

Title: Identification of conformational ensembles in solution: Potential source of bioactive candidates

Abstract: The success of medicinal chemistry is defined by the ability to create/enhance the affinity of drug-like agents to a receptor. The three-dimensional arrangement a drug takes on in the receptor pocket (or the drug\'s bioactive conformation) becomes a valuable source of data to guide the design and synthesis of future agents. A ligand cocrystallized with the receptor offers the most direct method of attaining the bioactive conformation. However, if no crystal structure exists or if the crystal is of low resolution, other means of attaining the bioactive conformation must be found. The hypothesis of this work is that solution conformations can be used as a list of potential bioactive candidates. A method known as NAMFIS (NMR Analysis of Molecular Flexibility In Solution), which uses geometric NMR data and force-field generated structures to generate a list of solution conformations at various populations, is employed to deconvolute the NMR into a set of structures that best reproduce the NMR data. The conformational analysis of a highly polar microtubule-stabilizing agent known as laulimalide is performed using the NAMFIS methodology. NAMFIS selected 15 conformations could be reduced to 5 structural families (motifs) to reproduce 79 NOE distances and 8 coupling constants. Additional statistical and energetic checks were performed to determine how likely each NAMFIS-selected conformation actually exists in solution. A NAMFIS analysis of two naturally occurring antibiotics (geldanamycin and radicicol) was also performed. Crystallographic analysis show that geldanamycin and radicicol share a common binding-site on a protein chaperone, known as Heat shock protein 90 (Hsp90). It was shown that NAMFIS-selected conformations that were virtually similar to the protein-bound x-ray conformations with population values of 4% (geldanamycin) and 21% (radicicol). Mammalian tubulin is known to bundle in the presence of Taxol. Yeast tubulin, which has 75% homology with mammalian tubulin, is unaffected by the presence of Taxol. Himes et al. has shown that five single-point mutations in yeast tubulin results in a Taxol-sensitive yeast strain. A NAMFIS-selected conformation of Taxol and a yeast homology model were scored to determine role each residue played in Taxol-tubulin binding.

MPACT Scores for Pahk Thepchatri

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2008-03-02 23:48:20

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