Search for approaches to improving the calculation accuracy of the protein-ligand binding energy by docking

The following reasons limiting the accuracy of calculations of the protein-ligand binding energy by the molecular docking programs are considered: the limited facilities of algorithms of finding a global minimum on a complicated multi-dimensional protein-ligand energy surface, restrictions on the degrees of freedom of a protein-ligand system including docking into a rigid protein, inadequacy of the existing force fields, a lack of taking into account the solvent or too rough allowance for the solvent in the docking procedure, a lack of the local energy optimization in the docking process, an inaccuracy of the construction of models of a target protein and a ligand, simplification of the calculation method of the Gibbs free energy of a molecular system, and limited computer resources for docking of one ligand. A new approach to the development of the new generation of docking programs is proposed. The approach allows one to remove step-by-step the existing simplifications and to increase considerably the accuracy of the whole docking process, including the calculation accuracy of the protein-ligand binding energy. The results of the study are presented and demonstrate the computational feasibility of the assigned docking problem.