PhD 2023-2026

Simulation of neonicotinoid properties in different environments

DESCRIPTION : PhD position in theoretical chemistry/ molecular modeling from september /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
https://ceisam.univ-nantes.fr/en/
CONTACTS : Jean-Yves Le Questel Jean-Yves.Le-Questel@univ-nantes.fr
Nicolas Galland nicolas.galland@univ-nantes.fr

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 7 isotype of the human nAChR1 (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

1
R. E. Hibbs et al., Cell 2021, doi : 10.1016/j.cell.2021.02.049
2
A. Bigot et al., Journal of Medicinal Chemistry, 2022, doi : 10.1021/acs.jmedchem.1c01767
 Figure 1. structural organization of an nAChR
a) b) 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 42 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.

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 nicolas.galland@univ-nantes.fr.

3
A. Cartereau, E. Taillebois, J.-Y. Le Questel and S.H. Thany Int. J. Mol. Sci. 2021, doi : 10.3390/ijms22189880
4
Z. Alamiddine, B. Selvam, J. Graton, A.D. Laurent, E. Landagaray, J. Lebreton, M. Mathe-Allainmat, S.H. Thany and J.-Y.
Le Questel, 2019, doi: 10.1021/acs.jcim.9b00272