Rational Design of Positive and Negative Allosteric Modulators of Glycine Receptors Function

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 GlyR’s 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 α1. The availability of atomistic models of GlyR α1 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.

Requirements:
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.

Remarks: 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 d’Ingenierie des Fonctions Moléculaires
UMR7177, 4, rue Blaise Pascal, 67000 Strasbourg
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[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. Lü, 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.

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