Advances in Docking Sulimov, Vladimir B; Kutov, Danil C; Sulimov, Alexey V
Current medicinal chemistry,
01/2019, Letnik:
26, Številka:
42
Journal Article
Recenzirano
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.
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.
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.
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.
The previously developed high-performance parallel method of the atomistic simulation of the ion beam sputtering deposition process is applied to the SiO2 thin films. Structural properties of ...deposited films such as density, concentration of point defects, ring statistics, as well as effects arising from the interaction of high energy sputtered Si atoms with the growing film are discussed.
•DESIL force field reproduces structure of glassy silica.•Deposited film density exceeds the density of glassy silica.•Concentration of the point defects decreases with thickness of film.•Film density increases with energy of the deposited atoms.
Docking Paradigm in Drug Design Sulimov, Vladimir B; Kutov, Danil C; Taschilova, Anna S ...
Current topics in medicinal chemistry,
01/2021, Letnik:
21, Številka:
6
Journal Article
Recenzirano
Docking is in demand for the rational computer aided structure based drug design. A review of docking methods and programs is presented. Different types of docking programs are described. They ...include docking of non-covalent small ligands, protein-protein docking, supercomputer docking, quantum docking, the new generation of docking programs and the application of docking for covalent inhibitors discovery. Taking into account the threat of COVID-19, we present here a short review of docking applications to the discovery of inhibitors of SARS-CoV and SARS-CoV-2 target proteins, including our own result of the search for inhibitors of SARS-CoV-2 main protease using docking and quantum chemical post-processing. The conclusion is made that docking is extremely important in the fight against COVID-19 during the process of development of antivirus drugs having a direct action on SARS-CoV-2 target proteins.
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 use of computer simulation methods has become an indispensable component in identifying drugs against the SARS-CoV-2 coronavirus. There is a huge body of literature on application of molecular ...modelling to predict inhibitors against target proteins of SARS-CoV-2. To keep our review clear and readable, we limited ourselves primarily to works that use computational methods to find inhibitors and test the predicted compounds experimentally either in target protein assays or in cell culture with live SARS-CoV-2. Some works containing results of experimental discovery of corresponding inhibitors without using computer modelling are included as examples of a success. Also, some computational works without experimental confirmations are also included if they attract our attention either by simulation methods or by databases used. This review collects studies that use various molecular modelling methods: docking, molecular dynamics, quantum mechanics, machine learning, and others. Most of these studies are based on docking, and other methods are used mainly for post-processing to select the best compounds among those found through docking. Simulation methods are presented concisely, information is also provided on databases of organic compounds that can be useful for virtual screening, and the review itself is structured in accordance with coronavirus target proteins.
Cardiovascular diseases caused by blood coagulation system disorders are one of the leading causes of morbidity and mortality in the world. Research shows that blood clotting factors are involved in ...these thrombotic processes. Among them, factor Xa occupies a key position in the blood coagulation cascade. Another coagulation factor, XIa, is also a promising target because its inhibition can suppress thrombosis with a limited contribution to normal hemostasis. In this regard, the development of dual inhibitors as new generation anticoagulants is an urgent problem. Here we report the synthesis and evaluation of novel potential dual inhibitors of coagulation factors Xa and XIa. Based on the principles of molecular design, we selected a series of compounds that combine in their structure fragments of pyrrolo3,2,1-ijquinolin-2-one and thiazole, connected through a hydrazine linker. The production of new hybrid molecules was carried out using a two-stage method. The reaction of 5,6-dihydropyrrolo3,2,1-ijquinoline-1,2-diones with thiosemicarbazide gave the corresponding hydrazinocarbothioamides. The reaction of the latter with DMAD led to the target methyl 2-(4-oxo-2-(2-(2-oxo-5,6-dihydro-4H-pyrrolo3,2,1-ijquinolin-1(2H)-ylidene)hydrazineyl)thiazol-5(4H)-ylidene)acetates in high yields. In vitro testing of the synthesized molecules revealed that ten of them showed high inhibition values for both the coagulation factors Xa and XIa, and the IC50 value for some compounds was also assessed. The resulting structures were also tested for their ability to inhibit thrombin.
Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better ...therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo3,2,1-
quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa.
A systematic study of the most significant parameters of the ion-assisted deposited silicon dioxide films is carried out using the classical molecular dynamics method. The energy of the deposited ...silicon and oxygen atoms corresponds to the thermal evaporation of the target; the energy of the assisting oxygen ions is 100 eV. It is found that an increase in the flow of assisting ions to approximately 10% of the flow of deposited atoms leads to an increase in density and refractive index by 0.5 g/cm3 and 0.1, respectively. A further increase in the flux of assisting ions slightly affects the film density and density profile. The concentration of point defects, which affect the optical properties of the films, and stressed structural rings with two or three silicon atoms noticeably decrease with an increase in the flux of assisting ions. The film growth rate somewhat decreases with an increase in the assisting ions flux. The dependence of the surface roughness on the assisting ions flux is investigated. The anisotropy of the deposited films, due to the difference in the directions of motion of the deposited atoms and assisting ions, is estimated using the effective medium approach.
An atomistic simulation of silicon dioxide thin films deposited using oxide targets is performed. The influence of the oxide target on the deposition process is taken into account by introducing ...O=Si=O molecules into the flow of particles moving from the target to the substrate. The fraction of these molecules varied from 0 to 50%. It was found that the presence of O=Si=O molecules leads to film densification during a normal deposition. With a low-energy deposition, the increase in density was twice as high as with a high-energy deposition. The absolute value of the compressive stress increased with an increasing fraction of O=Si=O molecules in the flow of deposited particles at a normal, high-energy deposition. The influence of O=Si=O molecules on the structure of the glancing angle deposited films depends on the deposition angle.
A virtual structure-oriented screening of candidates for inhibitors of blood coagulation factor XIIa was carried out. This coagulation factor is one of the most promising therapeutic targets for the ...development of anticoagulants without disturbing normal hemostasis. The screening was carried out in the database of organic compounds of the Voronezh State University, consisting of more than 19 thousand molecules. At the first stage of virtual screening, ligands were positioned in the active center of factor XIIa using the SOL docking program. At the second stage, for the best ligands, the protein-ligand binding enthalpy was calculated using the MOPAC program and the PM7 quantum-chemical method, taking into account the solvent in the COSMO continuum model. All calculations were carried out using the supercomputing resources at Lomonosov Moscow State University. In total, more than 30 thousand ligand conformers are docked, and for more than 400 of the best of them, the protein-ligand binding enthalpy was calculated. 16 compounds are selected as the most promising candidates for subsequent in vitro testing of their ability to inhibit factor XIIa.
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