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Date: Tue Sep 18 11:50:59 2018
Subject: 18.09.18 PhD opening - Rational Design of ligand-gated ion channel modulators (University of Strasbourg)
Pentameric ligand-gated ion channels (pLGICs) are neurotransmitter receptors that mediate the 
intercellular communication in the brain and the nervous system by converting a chemical signal 
into an ion current at chemical synapses [1]. Among them, Glycine receptors (GlyRs) play a critical 
role in motor coordination and essential sensory functions including vision and audition, and have 
been since long recognized as pharmacological targets for chronic pain, autism and the startle 
disease [2]. The rational design of small-molecule compounds able to activate, inhibit, or modulate 
GlyRs function is key for the development of new pharmacological strategies in humans. 
At the structural level, GlyR is by far the best-characterized pLGIC, since several high-resolution 
structures with modulatory ligands (agonist, antagonist, and modulators) and in different 
conformations have been recently deposited [3]. Also, recent simulation work by us [4] has 
contributed to the establishment of the 3D structure of the physiologically active state, providing 
a consistent functional annotation of anionic channel structures.

Goal(s): The ultimate goal of this PhD project is the discovery of novel allosteric modulators of the 
human GlyR 1. The availability of atomistic models of GlyR 1 in complex with agonists, antagonists, 
and modulators along with a consistent functional annotation put us in the privileged condition to 
study the pharmacology of the resting, active, and desensitized states. Following the MWC model of 
allostery [5], we will explore the opportunity to design positive (PAM) and negative (NAM) allosteric 
modulators by screening for compounds that maximize the differential binding affinity for one 
conformational state over the others. A fundamental aspect of the project is providing a proof of 
principle that this approach, here termed state-based pharmacology, is useful for the rational 
design of positive and negative allosteric modulators of ligand-gated ion channels. 

Responsibilities: The successful candidate will be in charge of homology modeling, 
explicit solvent/membrane Molecular Dynamics simulations, comparative analysis of the 
modulatory sites, docking, and virtual high-throughput screening. 
The latter will be performed with the in house software ChemFlow [6], 
which is designed for screening with free energy rescoring by Molecular Dynamics.

1.	Master degree in Chemistry, Biophysics, Bioinformatics, or related disciplines.
2.	Sound background in Physical Chemistry and Molecular Modeling.
3.	Strong interest in Drug Design.
4.	Proficiency in English.

This project is part of a broader research program (PENTA_CONTROL) carried out in collaboration 
with the experimental group of Pierre-Jean Corringer at Institut Pasteur (Paris), which was funded 
this year by the French National Research Agency (ANR), and is tightly connected with the Co-Design
 Project 6 (CDP6) of the Human Brain Project led by Jean-Pierre Changeux.

[1]	M. Cecchini, J.-P. Changeux, Neuropharmacology 2015, 96, 137.
[2]	S. Dutertre, C.-M. Becker, H. Betz, J. Biol. Chem. 2012, 287, 40216.
[3]	a) J. Du, W. L, S. Wu, Y. Cheng, E. Gouaux, Nature 2015, 526, 224; 
        b) X. Huang, H. Chen, P. L. Shaffer, Structure 2017, 25, 945; 
        c) X. Huang, H. Chen, K. Michelsen, S. Schneider, P. L. Shaffer, Nature 2015, 526, 277; 
        d) X. Huang, P. L. Shaffer, S. Ayube, H. Bregman, H. Chen, 
           S. G. Lehto, J. A. Luther, D. J. Matson, S. I. McDonough, 
           K. Michelsen, M. H. Plant, S. Schneider, J. R. Simard, 
           Y. Teffera, S. Yi, M. Zhang, E. F. DiMauro, J. Gingras, 
           Nat Struct Mol Biol 2017, 24, 108.
[4]	A. H. Cerdan, N. E. Martin, M. Cecchini, Structure 2018, in press.
[5]	J. Monod, J. Wyman, J. P. Changeux, Journal of molecular biology 1965, 12, 88.
[6]	D. Gomes, C. Bouysset, M. Cecchini, in preparation.
The position is available from October 1, for a maximal duration of 3 years. 
The salary is 1400 /month with possible variations based on experience. 
Only highly motivated candidates will be considered. Experience with in silico library screening 
and/or Molecular Dynamics simulations of biomolecules will be considered as an asset. 
Applications including a cover letter, list of exams with scores, CV, and one or two reference letters 
should be sent to :

Marco Cecchini, HDR 
Laboratoire dIngenierie des Fonctions Molculaires
UMR7177, 4, rue Blaise Pascal, 67000 Strasbourg
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