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Accueil du site > Jobs - PostDoc - These > post-doc opening on allosteric drug design — University of Strasbourg (France)

post-doc opening on allosteric drug design — University of Strasbourg (France)

par Nord & Ile de France - 10 juillet 2020

Towards rational design of allosteric modulators targeting the transmembrane domain of neurotransmitter receptors

Pentameric ligand-gated ion channels (pLGICs) are neurotransmitter receptors that mediate the intercellular communication in the brain and the nervous system [1]. Among them, Glycine receptors (GlyRs) play a critical role in motor coordination and essential sensory functions such as vision and audition, and have been since long recognized as pharmacological targets for chronic pain [2]. At the structural level, GlyRs are by fare the best- characterized pLGICs with several high-resolution structures solved in complex with modulatory ligands. Moreover, recent simulation analyses have provided a consistent structure to function annotation [3]. which is critical for the design of positive and negative modulators. A wide panel of small-molecule compounds including psychoactive drugs, general anesthetics, and neurotoxins regulate the function of GlyRs. Recently, a collection of 218 unique chemical entities with documented modulatory activity at GlyR and annotation of their ligand-binding site on the receptor has been published (GRALL) [4]. Remarkably, this analysis highlights that about one third of currently known modulators target the transmembrane domain of the receptor. Along with recent observations on the modulation of pLGICs by endogenous lipids [5], these findings highlight that relevance of the transmembrane domain for the design of new neuroactive compounds.

Goal(s) : The ultimate goal of this project is the development of effective computational approaches based on all-atom Molecular Dynamics to facilitate the design of positive and negative allosteric modulators of GlyR targeting the transmembrane domain. A fundamental aspect of the project is providing a proof of principle that the approach is able to identify the binding site of structurally annotated compounds targeting the transmembrane domain of GlyR, such as ivermectin or the brain neurosteroids pregnenolone sulfate and tetrahydro- deoxycorticosterone, and predict the location of structurally not- annotated modulators, such as the cannabinoids. The research will involve three levels of discovery : (1) a topographical mapping of the ligand-binding site(s) in the transmembrane domain by “flooding” simulations [6] ; (2) the calculation of the ligand-binding affinity (𝐾d) per site by efficient free energy methods [7] ; and (3) an analysis of the relative residence time (𝐾off) and dissociation mechanism by recent approaches based on enhanced sampling [8]. These studies will provide fundamental insights on the ligand-receptor interactions in the lipid membrane and guidelines for the conception of new allosteric modulators of brain receptors. Responsibilities : The successful candidate will be in charge of implementing an efficient protocol for preparing and running the flooding simulations using Gromacs. Binding affinity calculations will be carried out using the in house software ChemFlow [9], which implements an automated workflow for virtual screening with free energy rescoring. The analysis of the residence time of the ligands will be also done using Gromacs. An in-depth understanding of the key aspects determining both the ligand-binding affinity and the residence time of known modulators in the lipid membrane environment is expected to emerge.

Requirements : 1. PhD degree with a track record in computational biology or virtual screening. 2. Proficiency in modeling and simulations of proteins and management of HPC resources. 3. A strong interest in drug discovery. 4. A theoretical understanding of protein-ligand binding. 5. Proficiency in English both oral and written.

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). It is funded 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 September 1 for one year and renewable for two more years based on funding approval. The salary is 2160 €/month (after taxes). Only highly motivated candidates will be considered. Experience with in silico library screening and/or binding free energy calculations will be considered as an asset. Applications including a cover letter, a 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 mcecchini@unistra.fr [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) A. H. Cerdan, N. E. Martin, M. Cecchini, Structure 2018, 26, 1555 ; b) A. H. Cerdan, M. Cecchini, Structure 2020, 28, 690. [4] A. H. Cerdan, M. Sisquellas, G. Pereira, D. E. Barreto Gomes, J. P. Changeux, M. Cecchini, Bioinformatics 2020, 36, 3379. [5] A. L. Duncan, W. Song, M. S. P. Sansom, Annu Rev Pharmacol Toxicol 2020, 60, 31. [6] M. J. Arcario, C. G. Mayne, E. Tajkhorshid, J Biol Chem 2017, 292, 9480. [7] I. Massova, P. A. Kollman, Perspectives in drug discovery and design 2000, 18, 113. [8] D. B. Kokh, M. Amaral, J. Bomke, U. Gradler, D. Musil, H. P. Buchstaller, M. K. Dreyer, M. Frech, M. Lowinski, F. Vallee, M. Bianciotto, A. Rak, R. C. Wade, J Chem Theory Comput 2018, 14, 3859. [9] D. Gomes, C. Bouysset, M. Cecchini, in preparation.