This project has as its main goal a full understanding of the binding event, and of binding sites in proteins for at least three currently used anesthetic chemotypes, haloalkanes, haloethers and alkylphenols. This includes an understanding of the features underlying binding energetics (affinity) and selectivity, as well as a characterization of the distribution of such sites in specific proteins, like ion channels. We will accomplish these ambitious goals through two specific aims.
Aim 1 is to design, synthesize and characterize novel chemical tools to discover anesthetic binding sites in complex heteroligomeric ion channel proteins.
Aim 2 will deploy these tools, such as the very successful general anesthetic photolabels, in both ligand and voltage gated ion channels. This latter work both provides and directly tests hypotheses in the other projects. The long range goal is to understand features ofthe ligand and ofthe binding site that underlie selectivity so that the compounds can be altered to enhance on-pathway effects and/or to reduce off-pathway effects. Overall, project 1 is a translational conduit of program derived information to clinical relevance.

Public Health Relevance

General anesthetics are delivered to patients roughly 120 million times per year, world wide. They are the most toxic of all drugs physicians use, and have many troublesome side effects, some durable. This project seeks an understanding of their action through the binding event, and using this information will identify novel chemotypes as the basis for the next generation of general anesthetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM055876-14A1
Application #
8534420
Study Section
Special Emphasis Panel (ZGM1-PPBC-5 (AN))
Project Start
Project End
2018-05-31
Budget Start
2013-09-26
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$314,587
Indirect Cost
$115,480
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kinde, Monica N; Bondarenko, Vasyl; Granata, Daniele et al. (2016) Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac. Proc Natl Acad Sci U S A 113:13762-13767
Meng, Tao; Bu, Weiming; Ren, Xianfeng et al. (2016) Molecular mechanism of anesthetic-induced depression of myocardial contraction. FASEB J 30:2915-25
Elokely, Khaled; Velisetty, Phanindra; Delemotte, Lucie et al. (2016) Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc Natl Acad Sci U S A 113:E137-45
Granata, Daniele; Carnevale, Vincenzo (2016) Accurate Estimation of the Intrinsic Dimension Using Graph Distances: Unraveling the Geometric Complexity of Datasets. Sci Rep 6:31377
Kinde, Monica N; Bu, Weiming; Chen, Qiang et al. (2016) Common Anesthetic-binding Site for Inhibition of Pentameric Ligand-gated Ion Channels. Anesthesiology 124:664-73
Woll, Kellie A; Murlidaran, Sruthi; Pinch, Benika J et al. (2016) A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of γ-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes. J Biol Chem 291:20473-86
Woll, Kellie A; Dailey, William P; Brannigan, Grace et al. (2016) Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands. Anesth Analg 123:1253-1262
Carswell, Casey L; Hénault, Camille M; Murlidaran, Sruthi et al. (2015) Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels. Structure 23:1655-64
Woll, Kellie A; Weiser, Brian P; Liang, Qiansheng et al. (2015) Role for the propofol hydroxyl in anesthetic protein target molecular recognition. ACS Chem Neurosci 6:927-35
Cournia, Zoe; Allen, Toby W; Andricioaei, Ioan et al. (2015) Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory. J Membr Biol 248:611-40

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