Key words: three-dimensional quantitative structure-activity relationship, molecular dynamics, structure-based drug design, molecular docking
Computer simulation has become the third research method after experiment and theory, which is widely used in various scientific fields and develops rapidly. The same is true of drug design and molecular simulation. The general trend is that the calculation accuracy is getting higher and higher, and the combination with experiments is getting closer and closer. In recent years, China has made great progress in drug design and molecular simulation research. Among them, quantitative structure-activity relationship has been widely used in drug research and has become a powerful tool for drug structure transformation. With the rapid development of molecular simulation research and diversified calculation methods, the time and space scale of simulation is getting closer to the real system, and some high-level achievements have been made.
First, quantitative structure-activity relationship.
Quantitative structure-activity relationship (QSAR) is the earliest developed molecular design method. Once the quantitative relationship between biological activity and structure of known compounds is determined, researchers can modify the structure of compounds according to this relationship to obtain higher activity. 3D-QSAR (especially comparative molecular force field analysis) has become one of the most commonly used drug design methods because of its powerful predictive ability and intuitive model.
PPAR such as thiazolidinedione and aryl ketoacid? Excitative substances can enhance the signal transduction between insulin and its receptor and promote fat metabolism. The three-dimensional quantitative structure-activity relationship of these two compounds was studied by comparative molecular force field analysis, which revealed the reason why aromatic ketoacids were more active than thiazolidinediones, and speculated PPAR? When combined with these compounds, the shape of the active site may be different from that of rosiglitazone [1].
Di-tert-butylphenyl heterocyclic compounds are inhibitors of COX-2 and have anti-inflammatory effects. The three-dimensional quantitative structure-activity relationship of three heterocyclic compounds containing di-tert-butyl phenyl was studied. Among the three possible overlapping models, choose the best cross-validation result. The results show that the contribution of electrostatic interaction to the activity of the compound is slightly greater than that of van der Waals interaction. Increasing the positive charge of heterocyclic ring can improve the activity of compounds [2].
Farnesyl protein transferase inhibitors of 1- imidazolyl benzodiazepines were studied by using comparative molecular force field analysis. It was found that increasing the volume of substituents on benzodiazepine (caotouzhuo) benzene ring would reduce the activity of the compound, while increasing the volume of substituents on imidazole ring could improve the activity of the compound [3].
Pyridinone compounds are a kind of anti-inflammatory and analgesic drugs with great medicinal prospects. The quantitative relationship between anti-inflammatory activity and molecular structure of 5,6-diaryl substituted pyridones was studied by computer-aided drug design expert system (Apex-3D). The results showed that the activity of the compound was similar to that of the pyridone ring 1 substituent. The charge density is positively related to the hydrophobicity of molecules [4].
Comparative molecular force field analysis is used to analyze a group? Structure-activity relationship of hydroxybutenoic lactone endothelial hormone antagonist. In the calculation, besides electrostatic field and solid field, hydrogen bonding field is also introduced. The results show that the introduction of hydrogen bonding field can obviously improve the calculation results. In addition, the influence of lattice spacing and probe atom type on the calculation results is also studied [5].
The quantitative structure-activity relationship of 2 1 potassium ion channel opener was studied with a series of geometric structure parameters and logP values calculated by ClogP software as structural parameters. The results show that the distance between hydrogen bond acceptor atom and the center of hydrophobic part is HA-Hy, and the angle between the vertical line of aromatic ring center and the connecting line between aromatic ring center and hydrophobic part center is? It has a significant effect on arterial diastolic activity [6].
The three-dimensional pharmacophore model of tyrosine kinase inhibitor was obtained by CATALYST software. The skeletons of the two compounds studied are completely different, but the pharmacodynamic groups are similar, which shows that their binding modes are similar. The pharmacodynamic groups of these two compounds include hydrogen bond acceptor, hydrogen bond donor, aliphatic hydrophobic group and aromatic hydrophobic group. On this basis, the three-dimensional structure-activity relationship [7] was studied.
Using flavonoids as templates, the quantitative structure-activity relationship and ab initio calculation of a series of flavonoids were studied. According to the analysis results of CoMFA, CoMSIA and HQSAR and the calculation of electrostatic potential, a reasonable pharmacophore model was proposed, and a model of flavonoids binding to GABAA receptor was proposed [8].
Secondly, drug design based on structure.
Structure-based drug design is one of the methods to find new structural drug lead compounds, and there are more and more examples of using structure-based drug design methods to find active compounds in China. However, due to intellectual property rights and other reasons, few papers have been published in this field, so this paper can only introduce the development of methods.
On the basis of analyzing the crystal structure of the complex of known inhibitors and phospholipase A2, a new inhibitor was designed and its biological activity was predicted by SCORE program. Subsequently, chemical synthesis and pharmacological experiments were carried out, and the results showed that the designed two compounds had certain activities, and the experimental values were corresponding to the predicted values of SCORE [9].
The interaction model between protein pretreatment enzyme furin/kexin and leech inhibitor (eglin C) mutant was studied by homology modeling and sequence evolution trajectory analysis, and the * * * characteristics and differences of furin/kexin subfamily substrates/inhibitors were clarified. On this basis, the interface redesign strategy [10] was used to rationally redesign Flynn/Cushing inhibitor.
The method of dynamically assembling molecular modules was improved, including screening molecules produced by dynamically assembling molecular modules by using binding energy and solvent accessible surface area (SASA), and a classification method based on molecular similarity was developed. The method was tested with COX-2 and its selective inhibitor SC-558, and the crystal structure reproducibility increased from 16.7% to 58.8%[ 1 1]. F-DycoBlock is developed on the basis of DycoBlock. In the process of multi-copy random molecular dynamics, on the one hand, the flexibility of small molecular ligands is considered, and at the same time, the influence of the average field of small molecular ligands on macromolecules is considered, so the flexibility of protein can also be considered. COX-2 and HIV- 1 proteolytic enzyme were used to detect it [12].
Thirdly, molecular simulation.
Molecular simulation provides abundant information for elucidating the structure and biological function of biological macromolecules by simulating their structures and dynamic behaviors. Generally speaking, it is difficult to obtain this information by experimental methods, so molecular simulation has become an important means to study the structure and function of biological macromolecules.
Threading method has achieved some success in predicting the three-dimensional structure of target protein based on template protein with low homology, but it is still difficult to deal with those cases where the three-dimensional structure of template protein and target protein are similar, but the sequence of secondary structure is inconsistent. It is found that the prediction ability of the threading method can be significantly improved by properly adjusting the staggered secondary structure fragments in the target sequence in advance [13].
By Monte Carlo method, the conformational properties of eight different snake venom neurotoxin ⅲ ring sequences in free state and in combination with short-chain neurotoxin B were studied. It is found that long-distance interaction does affect the conformation and stability of protein surface ring, while short-distance interaction only provides candidate conformations, which must be screened by long-distance interaction [14].
BLIP is the best TEM- 1-? A protein inhibitor of internal amidase, one of its domains 1? The angular structure B 1 can be compared with TEM- 1-? The active site of endoamidase binds, thus inhibiting its activity. The conformation of B 1 in phosphate buffer solution was studied by circular dichroism, Fourier infrared spectroscopy and nuclear magnetic resonance spectroscopy. The results showed that B 1 was formed in the solution. Corner structure [15].
Molecular dynamics method was used to simulate porcine insulin dimer, and the electrostatic potential of the dimer was calculated by finite difference method of continuous medium model. The hydrophobicity of dimer was analyzed by solvent accessible surface, and the effects of different PH values on electrostatic effect and hydrophobic effect of dimer were investigated. The analysis shows that the electrostatic effect and hydrophobic effect of dimer are favorable under the condition of weak acid and weak base. When the PH value is 6.2, the hydrophobic effect of dimer is the best [16].
The conformation of camptothecin was searched by molecular dynamics method, and the conformation close to the crystal structure was optimized by AM 1, PM3 and ab initio method. The structure optimized by ab initio method is closer to the crystal structure, and the lactone part of camptothecin E forms intramolecular hydrogen bonds, which improves the reactivity of lactone bonds and makes them vulnerable to water-induced ring opening and lose their activity. The study also shows that the interaction between camptothecin and TopoI-DNA complex will destroy the intramolecular hydrogen bond, and the energy compensation is great [17, 18].
The relationship between amino acids and amino acids was analyzed by fast annealing evolutionary algorithm. The combination of cyclodextrin was simulated. The linear regression analysis of the binding constant and action energy of 14 inclusion complex shows that there is a good correlation between them. Through the analysis of action energy, it is found that van der Waals action plays a major role. For amino acids with different chirality and? -Can the function of cyclodextrin be explained comparatively? -Chiral selectivity of cyclodextrin [19].
The relative binding free energy of two hydroxamic acid inhibitors with MMP-3 was calculated by free energy perturbation method. The calculation of free energy adopts two methods: slow growth and fixed window growth, and both adopt bidirectional sampling strategy. The calculated binding free energy is in good agreement with the experimental value, and the important interaction between inhibitor and MMP-3 is analyzed from the trajectory of kinetic simulation [20].
The three-dimensional structure of tryptophan tRNA synthetase from Bacillus subtilis was obtained by homologous modeling. The analysis results show that the secondary structure of the synthetase contains 16? Spiral five? Folding, the only tryptophan Trp92 is located at the interface of two subunits. In addition, the binding site, active site and possible binding mode with tRNATrp were predicted [2 1].
The folding of protein is a process driven by free energy, and the natural protein conformation is in a thermodynamic low energy state. Based on the hypothesis that protein domain is a folding unit, protein domain, as an independent folding unit, is not only relatively compact in structure, but also relatively stable in energy. Therefore, it is reasonable to divide domains by folding free energy. Using the free energy expansion method, the domain analysis of 50 kinds of protein with different double domains was carried out, and most of the results were consistent with the literature. Although a few results are inconsistent with the literature, the division results of expansion free energy method may be more reasonable [22].
Brownian dynamics is used to simulate the combination of scorpion venom Lq2 and potassium channels. The three-dimensional structure of scorpion venom is taken from 22 structures determined by NMR experiments. The results show that only four structures can combine with potassium channels with high probability and good electrostatic interaction. Through the triplet contact analysis of the above four structures, the three-dimensional structure model of the complex was constructed, and the main interaction between Lq2 and potassium ion channel was determined [23].
Homologous modeling and molecular dynamics were used to model the three-dimensional structure of memapsin 2 proteolytic enzyme. The active site of memapsin 2 proteolytic enzyme is a kind of protein rich in? Supported by the folding domain, and the active site is connected to the folding domain by a helix. ? Tyr 132 in hairpin structure is the isomorphic feature of aspartic protease. Analysis shows that although the structure of M2 proteolytic enzyme is unique, it still belongs to the aspartic protease superfamily [24].
Fourthly, database and virtual filtering.
If enough information about the target and the compounds bound to the target has been mastered, the virtual screening of a large compound database is very attractive, and it can be used as a supplementary method of Qualcomm screening to find lead compounds. Recently, the DOCK program developed by Kuntz was parallelized on the supercomputer, which greatly accelerated the speed of database screening. By this method, a series of potassium ion channels were found from the database of commercial compounds and the database of natural products in China. Secretory enzymes and PPAR? Bioactive compounds such as targets. However, due to the patent application, the results have not yet been announced.
SCORE is a scoring function, including van der Waals interaction, metal coordination, hydrogen bonding, desolvation and conformational changes of small molecules, which is used to evaluate the binding conformation of small molecules with protein found in DOCK4. 200 protein-ligand complexes were tested by the program SCOREDOCK, which was obtained by combining two methods. It is found that SCORE can obviously improve the calculation accuracy of DOCK [25].
Through the mixed programming of Fortran PowerStation and Visual C++, the computer-aided screening of bioactive compounds (CASAC) running under DOS for studying the relationship between molecular structure and biological activity was transplanted to Windows system [26].
Based on XML (Extensible Markup Language), the database of marine natural products is constructed. At present, the database contains about 1 1000 kinds of marine natural compounds and their molecular structures, biological sources, biological activities, drug effects, physical and chemical parameters and references. Integration with XML is beneficial to database management, query, Web publishing, data exchange and future expansion, and now it has the function of Web retrieval [27, 28].
A molecular docking algorithm combining genetic algorithm and random search is proposed, which adopts the strategy of considering shape complementarity and energy optimization step by step. The test results of eight randomly selected complexes show that the calculated conformation and orientation are close to the crystal structure, and the minimum root mean square deviation is less than 1.0[29] in most cases.
5,6-diaryl substituted pyridone is a new class of anti-inflammatory and analgesic drugs. The mechanism of these compounds was studied by molecular docking method. From the results of molecular docking, ZZ- 122 is well combined with COX-2, electrostatic interaction and van der Waals interaction are negative, and van der Waals interaction is dominant. However, the conformation combined with COX- 1 is seriously distorted, and there is a strong van der Waals repulsion between them. These results indicate that these compounds may be better selective inhibitors of COX-2 [30].