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1.
Summary MEPSIM is a computational system which allows an integrated computation, analysis, and comparison of molecular electrostatic potential (MEP) distributions. It includes several modules. Module MEPPLA supplies MEP values for the points of a grid defined on a plane which is specified by a set of three points. The results of this program can easily be converted into MEP maps using third-parties graphical software. Module MEPMIN allows to find automatically the MEP minima of a molecular system. It supplies the cartesian coordinates of these minima, their values, and all the geometrical relationships between them (distances, angles, and dihedral angles). Module MEPCOMP computes a similarity coefficient between the MEP distributions of two molecules and finds their relative position that maximizes the similarity. Module MEPCONF performs the same process as MEPCOMP, considering not only the relative position of both molecules but also a conformational degree of freedom of one of them. The most recently developed module, MEPPAR, is another modification of MEPCOMP in order to compute the MEP similarity between two molecules, but only taking into account a particular plane. The latter module is particularly useful to compare MEP distributions generated by systems of aromatic rings. MEPSIM can use several wavefunction computation approaches to obtain MEP distributions. MEPSIM has a menu type interface to simplify the following tasks: creation of input files from output files of external programs (GAUSSIAN and AMPAC/MOPAC), setting the parameters for the current computation, and submitting jobs to the batch queues of the computer. MEPSIM has been coded in FORTRAN and its current version runs on VMS/VAX computers. 相似文献
2.
The field of computational chemistry, particularly as applied to drug design, has become increasingly important in terms of
the practical application of predictive modeling to pharmaceutical research and development. Tools for exploiting protein
structures or sets of ligands known to bind particular targets can be used for binding-mode prediction, virtual screening,
and prediction of activity. A serious weakness within the field is a lack of standards with respect to quantitative evaluation
of methods, data set preparation, and data set sharing. Our goal should be to report new methods or comparative evaluations
of methods in a manner that supports decision making for practical applications. Here we propose a modest beginning, with
recommendations for requirements on statistical reporting, requirements for data sharing, and best practices for benchmark
preparation and usage. 相似文献
5.
CDs are cyclic oligosaccharides consisting of α-d -glucopyranosyl units linked through 1,4-linkages, which are obtained from enzymatic degradation of starch. The coexistence of hydrophilic and hydrophobic regions in the same structure makes these macrocycles extremely versatile as complexing host with application in food, cosmetics, environmental, agriculture, textile, pharmaceutical, and chemical industries. Due to their inherent chirality, CDs have been also successfully used as chiral selectors in enantioseparation science, in particular, for CE enantioseparations. In the last decades, multidisciplinary approaches based on CE, NMR spectroscopy, X-ray crystallography, microcalorimetry, and molecular modeling have shed light on some aspects of recognition mechanisms underlying enantiodiscrimination. With the ever growing improvement of computer facilities, hardware and software, computational techniques have become a useful tool to model at molecular level the dynamics of diastereomeric associate formation to sample low-energy conformations, the binding energies between the enantiomer and the CD, and to profile noncovalent interactions contributing to the stability of CD/enantiomer association. On this basis, the aim of this review is to provide the reader with a critical overview on the applications of CDs in CE. In particular, the contemporary theory of the electrophoretic technique and the main structural features of CDs are described, with a specific focus on techniques, methods, and approaches to model CE enantioseparations promoted by native and substituted CDs. A systematic compilation of all published literature has not been attempted. 相似文献
6.
We investigate the classification performance of circular fingerprints in combination with the Naive Bayes Classifier (MP2D), Inductive Logic Programming (ILP) and Support Vector Inductive Logic Programming (SVILP) on a standard molecular benchmark dataset comprising 11 activity classes and about 102,000 structures. The Naive Bayes Classifier treats features independently while ILP combines structural fragments, and then creates new features with higher predictive power. SVILP is a very recently presented method which adds a support vector machine after common ILP procedures. The performance of the methods is evaluated via a number of statistical measures, namely recall, specificity, precision, F-measure, Matthews Correlation Coefficient, area under the Receiver Operating Characteristic (ROC) curve and enrichment factor (EF). According to the F-measure, which takes both recall and precision into account, SVILP is for seven out of the 11 classes the superior method. The results show that the Bayes Classifier gives the best recall performance for eight of the 11 targets, but has a much lower precision, specificity and F-measure. The SVILP model on the other hand has the highest recall for only three of the 11 classes, but generally far superior specificity and precision. To evaluate the statistical significance of the SVILP superiority, we employ McNemar's test which shows that SVILP performs significantly (p < 5%) better than both other methods for six out of 11 activity classes, while being superior with less significance for three of the remaining classes. While previously the Bayes Classifier was shown to perform very well in molecular classification studies, these results suggest that SVILP is able to extract additional knowledge from the data, thus improving classification results further. 相似文献
7.
Summary A combination of molecular modeling and molecular dynamics (MD) is used to determine a theoretical structure for neuropeptide Y (NPY). Starting with the X-ray structure for avian pancreatic polypeptide (APP), the substituted amino acids were mutated, the side chains oriented to local potential energy minima, and the entire structure minimized and subjected to an MD simulation. Comparison of the resulting NPY structure with APP X-ray and MD results showed secondary structural elements to be maintained and RMS fluctuations to be similar, although differences in both were observed. The approach presented offers a means to study the structure-function relationships of NPY and other similar polypeptides when combined with pharmacological measurements.Abbreviations NPY
Neuropeptide Y
- APP
Avian pancreatic polypeptide
- ABNR
Adopted-basis Newton Raphson
- MD
Molecular dynamics 相似文献
8.
The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens. 相似文献
9.
The design and development of supercritical carbon dioxide (sc-CO 2) based processes for production of pharmaceutical micro/nanoparticles is one of the interesting research topics of pharmaceutical industries owing to its attractive advantages. The solubility of drugs in sc-CO 2 at different temperatures and pressures is an essential parameter which should be determined for this purpose. Chloroquine as a traditional antirheumatic and antimalarial agent is approved as an effective drug for the treatment of Covid-19. Pishnamazi et al. (2021) measured the solubility of this drug in sc-CO 2 at the pressure range of 120–400 bar and temperature range of 308–338 K, and correlated the obtained data using some empirical models. In this work, a comprehensive computational approach was developed to more accurately study the supercritical solubility of Chloroquine. The thermodynamic models include two equations-of-state based models (Peng-Robinson and Soave-Redlich-Kowang) and two activity coefficient-based models (modified Wilson's and UNIQUAC)), as well as, a multi-layer perceptron neural network (MLPNN)) were used for this purpose. Also, molecular modeling was performed to study the electronic structure of Chloroquine and identify the potential centers of intermolecular interactions during the dissolution process. According to the obtained results, all of the theoretical models can predict Chloroquine solubility in sc-CO 2 with acceptable accuracy. Among these models, the MLPNN model possesses the highest precision with the lowest average absolute relative deviation (AARD%) of 1.76 % and the highest Radj value of 0.999. 相似文献
10.
A series of N-(4-aryloxyphenyl)phthalimides were synthesized and identified as new inhibitors of the cytochrome bc1 complex. Furthermore, results obtained from computational simulations indicated that 3e' should bind to the Q o site of the bc1 complex. 相似文献
11.
Density functional theory calculations were used to examine the formation of lithium halide and lithium alkoxide mixed aggregates with halomethyllithium carbenoids. These mixed aggregates may be the important intermediates in carbenoid reactions where lithium halides are formed as byproducts, or when the mixture has been exposed to small amounts of air. The calculations showed that in the gas phase and in THF solution, mixed dimers, trimers, and tetramers may coexist with free lithium carbenoids, depending on the lithium salt. The calculations also indicated that mixed aggregates may influence the activation free energies of cyclopropanation reactions of lithium carbenoids. 相似文献
12.
Carbon nanotubes (CNTs) are very promising materials to remove pollutants from the environment. To develop safe, efficient technologies, it is necessary to understand the mechanisms of interaction between CNTs and pollutants. This requires innovative, interdisciplinary approaches. Detailed chemical analysis of the CNTs along with computational modeling can provide important information about the mechanisms of interaction. If biological experiments are included in these studies, useful complementary information is obtained. To exemplify the use of this approach, we present a case study in which detailed calculations and the Salmonella mutagenicity assay were applied to elucidate how multi-walled CNTs interact with 1-nitropyrene, an important mutagenic pollutant. 相似文献
13.
The interaction between vinpocetine(VPC) and human serum albumin(HSA) in physiological buffer(pH 7.40) was investigated by fluorescence,FT-IR,UV-vis absorption and molecular modeling.VPC effectively quenched the intrinsic fluorescence of HSA via static quenching.The binding site number n and apparent binding constant K_a,corresponding thermodynamic parametersΔG,ΔH andΔS at different temperatures were calculated.The synchronous fluorescence and FT-IR spectra were used to investigate the structural change of HSA molecules with addition of VPC.Molecular modeling indicated that VPC could bind to the site I of HSA and hydrophobic interaction was the major acting force,which was in agreement with the binding mode study. 相似文献
14.
Combined ligand-based and target-based drug design approaches provide a synergistic advantage over either method individually. Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach. Utilizing a set of recently reported derivatives of salvinorin A, a structurally unique KOP receptor agonist, a pharmacophore model was developed that consisted of two hydrogen bond acceptor and three hydrophobic features. The model was cross-validated by randomizing the data using the CatScramble technique. Further validation was carried out using a test set that performed well in classifying active and inactive molecules correctly. Simultaneously, a bovine rhodopsin based “agonist-bound” hKOP receptor model was also generated. The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model. In addition, this model was in agreement with the mutation experiments carried out on KOP receptor. The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model. The docked scores correlated reasonably well with experimental p K
i values. It is hypothesized that the integration of these two independently generated models would enable a swift and reliable identification of new lead compounds that could reduce time and cost of hit finding within the drug discovery and development process, particularly in the case of GPCRs.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. 相似文献
15.
LU 25-109 (II) and WAL 2014 (talsaclidine, III) are two M1 muscarinic agonists chemically related to the natural substance arecoline (I). All these compounds have beneficial effects on memory and cognition in animals and humans, and they have been proposed in the treatment of Alzheimer's disease, but only III will likely find a place in therapy. In this work we have investigated the solid state structures of II and III, and the X-ray structures of the two molecules and of the parent compound I have been used to input a series of computational chemistry efforts. In particular, the X-ray geometries have been manipulated to model 20 molecular structures (1–20) which have been submitted to ab initio, semiempirical quantum mechanics and molecular mechanics calculations. The conformational space accessible to the 20 structures has been assessed by means of potential energy maps. The reactivities of 1–20 have been estimated by examining at the graphics terminal the composition and the extension of the frontier orbitals (HOMOs and LUMOs) and of the molecular electrostatic potential. The information obtained has been interpreted to explain the different degrees of activity shown by I–III. Our data indicate that III has better in vivo activity for its intermediate size, less polar surface, conformational rigidity and orientation of reactive domains. 相似文献
16.
Doubly-armed diazatetralactams constitute a new series of easily synthesized tetralactams. The structural study of the calcium complexes of their N, N′-dimethyl acetamido and (2-pyridylmethyl) derivatives was performed by IR, 1H, 13C NMR spectroscopies and molecular modeling. These complexes showed a C 2 symmetry and a high number (8–9) of coordination around the calcium atom. 相似文献
17.
Summary Hydrophobicity of methylquinolines was compared with their retention data measured on two stationary phases by reversed-phase HPLC, and with the experimental partition coefficients (log P). The influence of the substituent position on the hydrophobicity is discussed and a two-parameter correlation equation is proposed permitting the prediction of the log k values with help of the inductive and resonance effects. 相似文献
18.
The binding properties of amino phosphate ester derivatives, compound 1 and 2 with calf thymus DNA (CT-DNA) were investigated by UV spectra, fluorescence spectra, molecular modeling and isothermal titration calorimetry (ITC). The intrinsic binding constants Kb of compound 1 and 2 with CT-DNA were determined by fluorescence spectroscopy and ITC, respectively. The results indicated that the two compounds bind to CT-DNA with different binding affinity, which is in the order of compound 1 > compound 2. At the same time, fluorescence spectra suggested that the mechanism of the binding of the two compounds to CT-DNA is a static enhancing type. According to the ethidium bromide displacement experiments, UV spectra, molecular modeling and ITC studies, it can be concluded that compound 1 and 2 are intercalators that can slide into the G–C rich region of CT-DNA. Furthermore, ITC data showed that compound/DNA binding is enthalpy controlled. 相似文献
20.
The current study was set to discover selective Plasmodium falciparum phosphatidylinositol-4-OH kinase type III beta ( pfPI4KB) inhibitors as potential antimalarial agents using combined structure-based and ligand-based drug discovery approach. A comparative model of pfPI4KB was first constructed and validated using molecular docking techniques. Performance of Autodock4.2 and Vina4 software in predicting the inhibitor-PI4KB binding mode and energy was assessed based on two Test Sets: Test Set I contained five ligands with resolved crystal structures with PI4KB, while Test Set II considered eleven compounds with known IC50 value towards PI4KB. The outperformance of Autodock as compared to Vina was reported, giving a correlation coefficient ( R2) value of 0.87 and 0.90 for Test Set I and Test Set II, respectively. Pharmacophore-based screening was then conducted to identify drug-like molecules from ZINC database with physicochemical similarity to two potent pfPI4KB inhibitors –namely cpa and cpb. For each query inhibitor, the best 1000 hits in terms of TanimotoCombo scores were selected and subjected to molecular docking and molecular dynamics (MD) calculations. Binding energy was then estimated using molecular mechanics–generalized Born surface area (MM-GBSA) approach over 50 ns MD simulations of the inhibitor- pfPI4KB complexes. According to the calculated MM-GBSA binding energies, ZINC78988474 and ZINC20564116 were identified as potent pfPI4KB inhibitors with binding energies better than those of cpa and cpb, with Δ Gbinding ≥ −34.56 kcal/mol. The inhibitor- pfPI4KB interaction and stability were examined over 50 ns MD simulation; as well the selectivity of the identified inhibitors towards pfPI4KB over PI4KB was reported. 相似文献
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