Molecular modeling methodologies are efficient and powerful tools to complement experimental observations and predict the properties of original compounds. In this framework, quantum chemistry methods are well-suited for an accurate estimation of key physicochemical properties. Indeed, force field based procedures are not appropriate for a detailed description of ligand-receptor complexes. The combination of various theoretical approaches is therefore necessary in order to get a comprehensive and precise picture of the properties investigated.
In this presentation, through a selection of recent examples studied in our group, the strategy that we use, based on an approach combining a wide range of molecular modeling methods: (QM (DFT), homology modeling, docking, Molecular Dynamics, QM/QM’) and experimental observations, will be presented. This methodology will be applied to the elucidation of conformational and binding properties of neonicotinoids, insecticides targeting nicotinic acetylcholine Receptors (nAChR). First, conformational analyses of the ligands are carried out using Density Functional Theory (DFT) calculations in the isolated state and implicit (SMD) solvent (water, dichloromethane) models. The various conformers are then docked using an induced fit protocol into the binding site of Aplysia californica Acetylcholine Binding Protein (Ac-AChBP), the recognized surrogate of the ligand binding domain of insect nAChR or homology models. Relevant complexes are thereafter submitted to molecular dynamic (MD) simulations. In a last step, QM/QM' calculations are carried out to refine the description (geometries, energies) of the neonicotinoid- nAChR models interactions (Figure 1).