Sunday, December 15th 2019                           

MODES TEAM

Modelling and Spectroscopy

Detailed topic: Molecular interactions and ligands of biological interest :

 

Involved people : François Besseau (engineer), Nicolas Galland (Assistant Prof.), Jérôme Graton (Assistant Prof.), Anais Goupille (engineer), Adèle Laurent (CNRS researcher) Jean-Yves Le Questel (Prof.), Rui Sousa (PhD Student) and Zakaria Alamiddine (PhD student).

 

General overview

In the framework of this topic, our investigations focus essentially on the study of non-covalent interactions, in particular the hydrogen-bond (H-bond) and the halogen-bond, with two main directions:

(i) the measurement of thermodynamic and spectroscopic parameters and the molecular modelling of hydrogen-bonding interactions in model organic compounds, commercially available or synthesized by organic chemists teams with whom we collaborate

(ii) the determination of the structure and interactions of biological ligands in various environments, from the gas phase to the active site of their biological receptor(s) .

 

Axis-1: H-bond Interactions

Despite the huge amount of studies devoted to the H-bond in the literature, it is generally admitted that quantitative data relevant to the structural and chemical diversity encountered in organic compounds are still missing. Our investigations in this research axis fit into this context. From experimental measurements, we accurately quantify the H-bond (accepting/ donating) strength of organic groups relevant to medicinal chemistry. These observations are completed and rationalized in parallel by theoretical calculations. These studies have led in 2009 to the development of the p K BHX database, containing about 1400 experimental values corresponding to 1200 compounds in its current version. Between 2010-2015, the database has been purchased by several leading industrial companies in the pharmaceutical and agrochemical fields (Roche, Gilead, Vertex, Boehringer-Ingelheim, Sanofi, Bayer) and in the biotechnology area (Biogen Idec) as well as by several international academic labs (U.S.A., Spain, United-Kingdom, Germany, France). In the context of this project, measurements dedicated to the H-bond acidity (p K AHY ) of organic compounds are in progress .

The purpose of this axis is to provide to the scientific community a set of parameters describing accurately and homogeneously the H-bond basicity and acidity of the functional groups of organic chemistry from a dual experimental and theoretical approach. The success of the p K BHX database, both in the industrial and academic sectors, is a clear illustration of the interest and of the need for such parameters, in particular in the field of medicinal chemistry, but also in organic and supramolecular chemistry.

For more information, please have a look to this document , which gathers the main concepts related to the database and the contacts to get it.

 

Axis-2: Probing the influence of fluorination on physicochemical properties of organic compounds through experimental measurements and theoretical calculations

The success of fluorination to improve molecular properties has been convincingly demonstrated in a wide range of applications of the chemical industry (materials, pharmaceuticals, agrochemicals, fine chemicals), and new applications continue to be discovered. Fluorination of target compounds impacts on a very wide range of chemical, physical and pharmacological properties. Therefore, for successful planning and rationalisation of fluorine introduction, a comprehensive understanding of the multiple effects of fluorination is a prerequisite. Despite this recognized importance, research efforts that address this issue are comparatively scarce. This cross-disciplinary project, based on a collaboration between our team and Prof. Linclau's group, a recognised expert in organofluorine chemistry, is at the heart of this framework. We want to provide a comprehensive understanding and characterization of the fluorination influence via an original and multidisciplinary (organic synthesis - experimental and theoretical physical chemistry) approach including (i) the careful design of model compounds to probe specific effects, (ii) their synthesis, (iii) the measurement of their H-bond properties, and (iv) the rationalisation and interpretation of experimental results by quantum chemistry calculations.

The research hypothesis for this project is that fluorination influences hydrogen-bonding properties of functional groups by a number of effects, and that a comprehensive study of stereoelectronic, electrostatic, and inductive effects is required to reach an adequate understanding of this topic. In addition, conformational effects, expected to be very important with acyclic substrates, will be investigated.

In the framework of this project, we have recently reported an unexpected effect related to the introduction of fluorine in a range of conformationally restricted fluorohydrins. Thus, we have shown that statements in the literature such as “the ability of fluorine … as an inductive activator of a H-bond donor group” and “fluorination always increases H-bond acidity” are incorrect as general rules. Indeed, our results force the conclusion that contrary to current assumptions, fluorination can lead to a significant attenuation of alcohol H-bond acidity compared to the corresponding nonfluorinated alcohols. DFT calculations indicate that intramolecular F···HO interactions are responsible for the H-bond acidity attenuation, and it is most remarkable that these weak interactions outcompete the fluorine electron-withdrawing effect.

We have carried on these studies by an experimental and theoretical investigation of a series of benzyl alcohols. We have found that o-fluorination generally resulted in an increase in the H-bond acidity of the hydroxyl group, whereas a decrease is observed upon o,o'-difluorination. Computational analysis showed that the conformational landscapes of these compounds are strongly influenced by the presence of o-fluorine atoms. Intramolecular interaction descriptors based on AIM, NCI and NBO analyses reveal that, in addition to an intramolecular OH···F interaction, secondary CH···F and/or CH···O interactions also occur, contributing to the stabilisation of the various conformations, and influencing the overall H-bond properties of the alcohol group.

This project, in essence of fundamental research, has applications in numerous fields connected to chemistry. Its ultimate goal is the development of a reliable predictive tool of the effect of fluorination on key physicochemical properties of organic molecules with functional groups relevant to medicinal chemistry, especially of H-bond properties, as well as in the establishment of correlations with associated properties such as lipophilicity and protonation acidity/basicity.

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Axis-3: Ligands of biological interest

The studies carried out within the frame of this topic are devoted to a comprehensive description of the structural features and non-covalent interactions of biological ligands in various environments , from the gas phase to the active site of their biological(s) receptor(s). Approaches combining measurements or analyses of experimental data taken from structural databases (Cambridge Structural Database (CSD), protein data bank (PDB)) and the application of various molecular modelling tools are used.

Since two years, our efforts in this thematic are devoted to the study of the interactions of neonicotinoids , one of the most widely used insecticide class in the world, and insects nicotinic acetylcholine receptors (nAChRs) . This leading place of neonicotinoids finds its origin in their competitive safety profile, high target specificity (for insects (nAChRs) with respect to mammals ones), and versatility in application methods. However, several studies have pointed out their adverse effects, in combination with other factors, on non-target invertebrate species, in particular on pollinators such as bees. The design of new representatives of this class of insecticides, more selective of pests and devoid of adverse effects, is therefore an important issue that requires the implementation of multiscale (cellular, molecular, atomic) and multidisciplinary (biology (electrophysiology, toxicology), chemistry (organic chemistry, theoretical chemistry)) approaches. This research project is at the heart of this framework and is based on such a multidisciplinary partnership with complementary skills. Thus, in collaboration with a neurobiologist team (Prof. Steeve Thany, Université d'Orléans) and a group of organic chemists (Prof. Jacques Lebreton and Dr. Monique Mathé-Allainmat, CEISAM) our aim is to understand, at complementary scales, the selectivity of neonicotinoids compounds for pests (cockroach) and pollinators (honeybee) neuronal nAChRs with the ultimate goal of designing new efficient, selective and safe insecticides.

 

L'objectif de ce projet est, à travers l'intégration de données multi échelle (de la molécule à la cellule) issues de différentes disciplines (électrophysiologie, chimie théorique et chimie organique), d'aboutir à une compréhension approfondie de la reconnaissance de ces ligands par les nAChRs dans le but de concevoir de façon rationnelle de nouveaux composés plus sélectifs des insectes nuisibles, plus efficaces et dénués d'effets toxiques.