Mots-Clés

interaction energy

Description

Virtual screening and docking-scoring methods are essential in preselecting hit molecules for pharmacological targets among millions of compounds. Structure-based methods aim to select the best potential hits for in vitro assays. Docking and scoring remain currently a major challenge in retrieving the true ligands, in terms of pose and ranking.

To address these issues, the goal of our project is to develop novel accurate empirical scoring functions, relying on physics-based terms to predict protein-ligand binding. The CRM2 laboratory is developing MoProSuite, a crystallography and molecular modeling software package for the analysis of the 3D structure and electron density distribution of molecules, and their related properties.  MoProViewer is molecular viewer GUI which includes many tools to compute molecular properties. MoProCmdLine is a command line version of the MoProViewer program which allows batch computation of interaction energies on large series of protein-ligand complexes (docking poses). This module is especially developed (in C++) for the development of our scoring function.

The energy function in the MoProCmdLine program includes an electrostatic energy term,  van der Waals potentials (dispersion+repulsion). Moreover, a solvation energy based on estimations of solvent accessible surface variation upon ligand binding is also computed. The entropic contribution to the Gibbs free energy variation is based on the enumeration of ligand conformational degrees of freedom.

 The internship will consist in the following tasks:

(1) Generate the energy data for a series of protein/ligand complexes including the native and docked poses.

(2) Critical analysis of the data and comparison with scores from docking programs and experiment affinity constants  

(3) Optional : possibility to program in C++ or fortran95 in our  software.