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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZGM1-PPBC-5)
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University of Pennsylvania
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Weiser, Brian P; Bu, Weiming; Wong, David et al. (2014) Sites and functional consequence of VDAC-alkylphenol anesthetic interactions. FEBS Lett 588:4398-403
Bu, Weiming; Pereira, Luis M; Eckenhoff, Roderic G et al. (2014) Stereoselectivity of isoflurane in adhesion molecule leukocyte function-associated antigen-1. PLoS One 9:e96649
Hénin, Jérôme; Salari, Reza; Murlidaran, Sruthi et al. (2014) A predicted binding site for cholesterol on the GABAA receptor. Biophys J 106:1938-49
Tronin, Andrey Y; Nordgren, C Erik; Strzalka, Joseph W et al. (2014) Direct evidence of conformational changes associated with voltage gating in a voltage sensor protein by time-resolved X-ray/neutron interferometry. Langmuir 30:4784-96
Chiara, David C; Gill, Jonathan F; Chen, Qiang et al. (2014) Photoaffinity labeling the propofol binding site in GLIC. Biochemistry 53:135-42
Palovcak, Eugene; Delemotte, Lucie; Klein, Michael L et al. (2014) Evolutionary imprint of activation: the design principles of VSDs. J Gen Physiol 143:145-56
Weiser, Brian P; Salari, Reza; Eckenhoff, Roderic G et al. (2014) Computational investigation of cholesterol binding sites on mitochondrial VDAC. J Phys Chem B 118:9852-60
Weiser, Brian P; Woll, Kellie A; Dailey, William P et al. (2014) Mechanisms revealed through general anesthetic photolabeling. Curr Anesthesiol Rep 4:57-66
Yuki, Koichi; Bu, Weiming; Xi, Jin et al. (2013) Propofol shares the binding site with isoflurane and sevoflurane on leukocyte function-associated antigen-1. Anesth Analg 117:803-11
Raju, S G; Barber, Annika F; LeBard, David N et al. (2013) Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. PLoS Comput Biol 9:e1003090

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