Background: Design of small molecules which are able to bind to the protein responsible for a disease is the key step of the entire process of the new medicine discovery. Atomistic computer modeling can significantly improve effectiveness of such design. The accurate calculation of the free energy of binding a small molecule (a ligand) to the target protein is the most important problem of such modeling. Docking is one of the most popular molecular modeling methods for finding ligand binding poses in the target protein and calculating the protein-ligand binding energy. This energy is used for finding the most active compounds for the given target protein. This short review aims to give a concise description of distinctive features of docking programs focusing on computation methods and approximations influencing their accuracy. Methods: This review is based on the peer-reviewed research literature including author’s own publications. The main features of several representative docking programs are briefly described focusing on their characteristics influencing docking accuracy: force fields, energy calculations, solvent models, algorithms of the best ligand pose search, global and local optimizations, ligand and target protein flexibility, and the simplifications made for the docking accelerating. Apart from other recent reviews focused mainly on the performance of different docking programs, in this work, an attempt is made to extract the most important functional characteristics defining the docking accuracy. Also a roadmap for increasing the docking accuracy is proposed. This is based on the new generation of docking programs which have been realized recently. These programs and respective new global optimization algorithms are described shortly. Results: Several popular conventional docking programs are considered. Their search of the best ligand pose is based explicitly or implicitly on the global optimization problem. Several algorithms are used to solve this problem, and among them, the heuristic genetic algorithm is distinguished by its popularity and an elaborate design. All conventional docking programs for their acceleration use the preliminary calculated grids of protein-ligand interaction potentials or preferable points of protein and ligand conjugation. These approaches and commonly used fitting parameters restrict strongly the docking accuracy. Solvent is considered in exceedingly simplified approaches in the course of the global optimization and the search for the best ligand poses. More accurate approaches on the base of implicit solvent models are used frequently for more careful binding energy calculations after docking. The new generation of docking programs are developed recently. They find the spectrum of low energy minima of a protein-ligand complex including the global minimum. These programs should be more accurate because they do not use a preliminary calculated grid of protein-ligand interaction potentials and other simplifications, the energy of any conformation of the molecular system is calculated in the frame of a given force field and there are no fitting parameters. A new docking algorithm is developed and fulfilled specially for the new docking programs. This algorithm allows docking a flexible ligand into a flexible protein with several dozen mobile atoms on the base of the global energy minimum search. Such docking results in improving the accuracy of ligand positioning in the docking process. The adequate choice of the method of molecular energy calculations also results in the better docking positioning accuracy. An advancement in the application of quantum chemistry methods to docking and scoring is revealed. Conclusion: The findings of this review confirm the great demand in docking programs for discovery of new medicine substances with the help of molecular modeling. New trends in docking programs design are revealed. These trends are focused on the increase of the docking accuracy at the expense of more accurate molecular energy calculations without any fitting parameters, including quantum-chemical methods and implicit solvent models, and by using new global optimization algorithms which make it possible to treat flexibility of ligands and mobility of protein atoms simultaneously. Finally, it is shown that all the necessary prerequisites for increasing the docking accuracy can be accomplished in practice.

Results of the combined use of the classical force field and the recent quantum chemical PM7 method for docking are presented. Initially the gridless docking of a flexible low molecular weight ligand into the rigid target protein is performed with the energy function calculated in the MMFF94 force field with implicit water solvent in the PCM model. Among several hundred thousand local minima, which are found in the docking procedure, about eight thousand lowest energy minima are chosen and then energies of these minima are recalculated with the recent quantum chemical semiempirical PM7 method. This procedure is applied to 16 test complexes with different proteins and ligands. For almost all test complexes such energy recalculation results in the global energy minimum configuration corresponding to the ligand pose near the native ligand position in the crystalized protein-ligand complex. A significant improvement of the ligand positioning accuracy comparing with MMFF94 energy calculations is demonstrated.

The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB. Each function was tested on the same set of 16 protein-ligand complexes. For exhaustive low-energy minima search the novel MPI parallelized docking program FLM and large supercomputer resources were used. Protein-ligand binding energies calculated using low-energy minima were compared with experimental values. It was demonstrated that the docking target function on the base of the MMFF94 force field in vacuo can be used for discovery of native or near native ligand positions by finding the low-energy local minima spectrum of the target function. The importance of solute-solvent interaction for the correct ligand positioning is demonstrated. It is shown that docking accuracy can be improved by replacement of the MMFF94 force field by the new semiempirical quantum-chemical PM7 method.

In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs. After validation of molecular modeling methods on well-known factor Xa inhibitors the virtual screening of NCI Diversity and Voronezh State University databases of ready-made low molecular weight species has been carried out. Seventeen compounds selected on the basis of modeling results have been tested experimentallyin vitro. It has been found that 12 of them showed activity against factor Xa (IC₅₀= 1.8–40 μM). Based on analysis of the results, the new original compound was synthesized and experimentally verified. It shows activity against factor Xa with IC₅₀value of 0.7 μM.