CDD · Thèse · 36 mois Bac+5 / Master laboratoire CEISAM, UMR 6230, Nantes Université, CNRS · NANTES (France)
Date de prise de poste : 1 octobre 2023
Homology modeling molecular docking molecular dynamics quantum chemistry neonicotinoids nicotinic acetylcholine receptors
DESCRIPTION: PhD position in structural bioinformatics/molecular modeling/ theoretical chemistry from october 2023.
Funding: Doctoral contract from the Ministry of Higher Education and Research (MESR)
LOCATION : ModES (Modeling & Spectroscopy) team, CEISAM laboratory, UMR 6230, Nantes Université, CNRS
CONTACTS : Jean-Yves Le Questel Jean-Yves.Le-Questel@univ-nantes.fr
Nicolas Galland firstname.lastname@example.org
CONTEXT AND OBJECTIVE
The growth of the world's population has created a major challenge for agricultural production: protecting crops from insect pests while preserving the environment. Faced with these challenges, the agrochemical industry has developed new insecticides that have proven to be toxic to non-target species more or less quickly after they were put on the market. In this context, neonicotinoids appeared very promising because of their specificity for insects and their lower toxicity compared to organophosphates and organochlorine pesticides. However, they are now considered to be deleterious, in particular to pollinating insects such as bees. Moreover, recent data have also shown a harmful effect on mammals, in particular humans. The understanding of the toxicity of these insecticides requires the characterization of their lipophilicity, an essential parameter to understand their effect on the cellular membrane system, and the precise description of their interactions with their target receptors. The thesis offer is located in the heart of this context, and will be part of a project funded by ANSES (French Agency for Food, Environmental and Occupational Health & Safety), established in partnership with a team of neurobiologists from the University of Orleans (Prof. Steeve Thany).
The thesis work will be devoted to the study of the toxicity of neonicotinoids through two levels of approaches, each with its own objectives.
Part of the work will be devoted to studying the interaction of these compounds with nicotinic acetylcholine receptors (nAChRs). Information on the three-dimensional structure of the binding site is available, notably for the alpha7 isotype of the human nAChR (1) (Figure 1), and in the case of a model of the extracellular binding domain of nAChRs, AChBP (Acetylcholine Binding Protein) cocrystallized with several neonicotinoids. (2)
Figure 1. structural organization of an nAChR a) overview showing, from top to bottom, the extracellular, transmembrane and intracellular domains, b) detail showing the ligand binding zone, located at the interface of subunits of the extracellular domain.
In addition to the bee nAChRs, the alpha4beta2 rat receptors will be modeled in order to rationalize the electrophysiology measurements performed at the University of Orleans. Some mutants of these systems that have been studied experimentally could also be studied using the same approach. For the bee and the rat, no crystallographic structure of nAChR being available, homology models will have to be developed. Molecular docking studies will determine the best orientation of the ligands in their binding sites and molecular dynamics simulations will examine the temporal evolution of the different complexes. This information will allow us to estimate the binding energies of each neonicotinoid to the targeted nAChRs and to establish a relative ranking of these insecticides for these receptors. We have recently shown the effectiveness of this type of approach for other isotypes of nAChRs or their models. (3,4)
In parallel, quantum calculations based on density functional theory (DFT) will be implemented to estimate the lipophilicity, from octanol/water partition coefficients, of a series of compounds acting as competitive modulators of nAChRs. This series will include neonicotinoids and other more recent ligands of nAChRs (sulfoximines, fluypyradifurone). Several levels of theory (DFT functional, basis set, solvent models) will be tested in a benchmark approach to determine the methodology leading to the most accurate predictions. These calculations will allow to estimate the relative affinity of neonicotinoids for the cell membrane system.
The thesis will be conducted in close collaboration with the team of neurobiologists of the University of Orleans involved in electrophysiological measurements and pharmacological studies associated with the same ligand-nAChRs systems.
PROFILE OF THE CANDIDATE
The proposed research topic, interdisciplinary from its context and applications, will implement a wide range of molecular modeling methods (quantum chemistry methods, homology modeling, molecular docking, molecular dynamics). The candidate should therefore have a strong background in these fields and in the chemistry-biology interface, especially in chemoinformatics methods used for the development and rationalization of the effects of biologically active molecules. Applicants should send a detailed CV, specifying grades or honors obtained in undergraduate and graduate degrees at the University, give references of two persons to contact in support of their application and a letter of motivation to Jean-Yves.Le-Questel@univ-nantes.fr and email@example.com.
Procédure : Please send the documents specified in the above description in the "Profile of the candidate" section to Jean-Yves Le Questel (Jean-Yves.Le-Questel@univ-nantes.fr) and Nicolas Galland (firstname.lastname@example.org)
Date limite : 15 juin 2023
Jean-Yves Le Questel et Nicolas Galland
Offre publiée le 8 février 2023, affichage jusqu'au 15 juin 2023