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Application of Solid State Nuclear Magnetic Resonance in Drug Discovery

Title: Application of Solid State Nuclear Magnetic Resonance in Drug Discovery.
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Inaccessible until Aug 29, 2018 due to copyright restrictions.

Name(s): Wright, Anna Kozlova, author
Cross, Timothy A., professor directing dissertation
Dudley, Gregory B., university representative
Blaber, Michael, committee member
Marshall, Alan G. (Alan George), committee member
Keller, Thomas C. S., committee member
Florida State University, degree granting institution
College of Arts and Sciences, degree granting college
Program in Molecular Biophysics, degree granting department
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2015
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
Physical Form: online resource
Extent: 1 online resource (117 pages)
Language(s): English
Abstract/Description: The M2 proton channel from Influenza A is an established drug target, with multiple functions during the viral lifecycle. Amino acid mutations, in the residues lining the channel pore, have rendered M2 resistant to previously licensed inhibitors. Given the propensity for genetic reassortment of Influenza A and history of pandemics due to emergence of novel human strains, M2 has been subject of numerous structural characterization efforts. Attempts at rational drug design targeting M2 proton channel have been impeded by the limited number of experimental techniques having capabilities for elucidating atomic level interactions of the protein-ligand complexes in the native-like membrane mimetic environment. Solid state Nuclear Magnetic Resonance (ssNMR) is a technique that has all of these capabilities for structural characterization of membrane protein drug targets in lipid bilayers. Coupling ssNMR with Computer Aided Drug Discovery (CADD) is the precise approach needed to decrease time and resources required to generate novel therapeutics. Here, we present a first structural characterization of the full length wild type M2 channel in complex with inhibitor, and of the S31N mutant in the apo and drug-bound state. Through the use of diverse ssNMR experiments we tested stereoselectivity of drug binding in the channel pore, structural changes due to mutation, and characterized novel inhibitor interactions. Molecular dynamic simulations were performed by our collaborators and were in good agreement with our experimental findings. Together these results deepen our understanding of the atomic level interactions stabilizing wild type inhibitors in the channel pore, and structural changes in the mutant leading to loss of compound efficacy. Most importantly, specific interaction described herein are essential for successful outcomes from structure based CADD and be used in future computational efforts.
Identifier: FSU_2016SP_Wright_fsu_0071E_13033 (IID)
Submitted Note: A Dissertation submitted to the Institute of Molecular Biophysics in partial fulfillment of the Doctor of Philosophy.
Degree Awarded: Fall Semester 2015.
Date of Defense: December 7, 2015.
Keywords: Drug Discovery, Influenza A, M2, membrane proteins, NMR, solid state
Bibliography Note: Includes bibliographical references.
Advisory Committee: Timothy Cross, Professor Directing Dissertation; Gregory B. Dudley, University Representative; Michael Blaber, Committee Member; Alan G. Marshall, Committee Member; Thomas C. S. Keller, Committee Member.
Subject(s): Biochemistry
Molecular dynamics
Chemistry, Physical and theoretical
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_2016SP_Wright_fsu_0071E_13033
Owner Institution: FSU

Choose the citation style.
Wright, A. K. (2015). Application of Solid State Nuclear Magnetic Resonance in Drug Discovery. Retrieved from http://purl.flvc.org/fsu/fd/FSU_2016SP_Wright_fsu_0071E_13033