共查询到20条相似文献,搜索用时 468 毫秒
1.
Summary A 115 compound dataset for HSA binding is divided into the training set and the test set based on molecular similarity and
cluster analyses. Both Kier–Hall valence connectivity indices and 4D-fingerprint similarity measures were applied to this
dataset. Four different predictive schemes (SM, SA, SR, SC) were applied to the test set based on the similarity measures
of each compound to the compounds in the training set. The first algorithmic scheme (SM) predicts the binding affinity of
a test compound using only the most similar training set compound’s binding affinity. This scheme has relatively poor predictivity
based both on Kier–Hall valence connectivity indices similarity measures and 4D-fingerprints similarity analyses. The other
three algorithmic schemes (SM SR, SC), which assign a weighting coefficient to each of the top-ten most similar training set
compounds, have reasonable predictivity of a test set. The algorithmic scheme which categorizes the most similar compounds
into different weighted clusters predicts the test set best. The 4D-fingerprints provide 36 different individual IPE/IPE type
molecular similarity measures. This study supports that some types of similarity measures are highly similar to one another
for this dataset. Both the Kier–Hall valence connectivity indices similarity measures and the 4D-fingerprints have nearly
same predictivity for this particular dataset. 相似文献
2.
Repasky MP Murphy RB Banks JL Greenwood JR Tubert-Brohman I Bhat S Friesner RA 《Journal of computer-aided molecular design》2012,26(6):787-799
Glide SP mode enrichment results for two preparations of the DUD dataset and native ligand docking RMSDs for two preparations of the Astex dataset are presented. Following a best-practices preparation scheme, an average RMSD of 1.140 ? for native ligand docking with Glide SP is computed. Following the same best-practices preparation scheme for the DUD dataset an average area under the ROC curve (AUC) of 0.80 and average early enrichment via the ROC (0.1?%) metric of 0.12 were observed. 74 and 56?% of the 39 best-practices prepared targets showed AUC over 0.7 and 0.8, respectively. Average AUC was greater than 0.7 for all best-practices protein families demonstrating consistent enrichment performance across a broad range of proteins and ligand chemotypes. In both Astex and DUD datasets, docking performance is significantly improved employing a best-practices preparation scheme over using minimally-prepared structures from the PDB. Enrichment results for WScore, a new scoring function and sampling methodology integrating WaterMap and Glide, are presented for four DUD targets, hivrt, hsp90, cdk2, and fxa. WScore performance in early enrichment is consistently strong and all systems examined show AUC?>?0.9 and superior early enrichment to DUD best-practices Glide SP results. 相似文献
3.
Hu G Kuang G Xiao W Li W Liu G Tang Y 《Journal of chemical information and modeling》2012,52(5):1103-1113
Virtual screening (VS) can be accomplished in either ligand- or structure-based methods. In recent times, an increasing number of 2D fingerprint and 3D shape similarity methods have been used in ligand-based VS. To evaluate the performance of these ligand-based methods, retrospective VS was performed on a tailored directory of useful decoys (DUD). The VS performances of 14 2D fingerprints and four 3D shape similarity methods were compared. The results revealed that 2D fingerprints ECFP_2 and FCFP_4 yielded better performance than the 3D Phase Shape methods. These ligand-based methods were also compared with structure-based methods, such as Glide docking and Prime molecular mechanics generalized Born surface area rescoring, which demonstrated that both 2D fingerprint and 3D shape similarity methods could yield higher enrichment during early retrieval of active compounds. The results demonstrated the superiority of ligand-based methods over the docking-based screening in terms of both speed and hit enrichment. Therefore, considering ligand-based methods first in any VS workflow would be a wise option. 相似文献
4.
Saltuk M. Eyrilmez Cemal Köprülüoğlu Dr. Jan Řezáč Prof. Pavel Hobza 《Chemphyschem》2019,20(21):2759-2766
This paper describes the excellent performance of a newly developed scoring function (SF), based on the semiempirical QM (SQM) PM6-D3H4X method combined with the conductor-like screening implicit solvent model (COSMO). The SQM/COSMO, Amber/GB and nine widely used SFs have been evaluated in terms of ranking power on the HSP90 protein with 72 biologically active compounds and 4469 structurally similar decoys. Among conventional SFs, the highest early and overall enrichment measured by EF1 and AUC% obtained using single-scoring-function ranking has been found for Glide SP and Gold-ASP SFs, respectively (7, 75 % and 3, 76 %). The performance of other standard SFs has not been satisfactory, mostly even decreasing below random values. The SQM/COSMO SF, where P−L structures were optimised at the advanced Amber level, has resulted in a dramatic enrichment increase (47, 98 %), almost reaching the best possible receiver operator characteristic (ROC) curve. The best SQM frame thus inserts about seven times more active compounds into the selected dataset than the best standard SF. 相似文献
5.
Empirical scoring functions used in protein-ligand docking calculations are typically trained on a dataset of complexes with
known affinities with the aim of generalizing across different docking applications. We report a novel method of scoring-function
optimization that supports the use of additional information to constrain scoring function parameters, which can be used to
focus a scoring function’s training towards a particular application, such as screening enrichment. The approach combines
multiple instance learning, positive data in the form of ligands of protein binding sites of known and unknown affinity and
binding geometry, and negative (decoy) data of ligands thought not to bind particular protein binding sites or known not to bind in particular geometries. Performance of the method for the Surflex-Dock scoring function is shown in cross-validation
studies and in eight blind test cases. Tuned functions optimized with a sufficient amount of data exhibited either improved
or undiminished screening performance relative to the original function across all eight complexes. Analysis of the changes
to the scoring function suggest that modifications can be learned that are related to protein-specific features such as active-site
mobility. 相似文献
6.
Vinh NB Simpson JS Scammells PJ Chalmers DK 《Journal of computer-aided molecular design》2012,26(4):409-423
We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening
was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic
core substituted by pyridine and fluorophenyl rings (structurally related to SB203580) and a set of decoy compounds. Multiple
protonation states and tautomers of active and decoy compounds were considered. Each docking model was evaluated using receiver
operating characteristic (ROC) curves and enrichment factors. The two best performing single crystal structures were found
to be 1BL7 and 2EWA, with enrichment factors of 14.1 and 13.0 at 2 % of the virtual screen respectively. Ensembles of up to
four receptors of similar conformations were generated, generally giving good or very good performances with high ROC AUCs
and good enrichment. The 1BL7-2EWA ensemble was able to outperform each of its constituent receptors and gave high enrichment
factors of 17.3, 12.0, 8.0 at 2, 5 and 10 % respectively, of the virtual screen. A ROC AUC of 0.94 was obtained for this ensemble.
This method may be applied to other proteins where there are a large number of inhibitor classes with different binding site
conformations. 相似文献
7.
Hsieh JH Wang XS Teotico D Golbraikh A Tropsha A 《Journal of computer-aided molecular design》2008,22(9):593-609
8.
Yoon S Smellie A Hartsough D Filikov A 《Journal of computer-aided molecular design》2005,19(7):483-497
Summary Structure-based screening using fully flexible docking is still too slow for large molecular libraries. High quality docking
of a million molecule library can take days even on a cluster with hundreds of CPUs. This performance issue prohibits the
use of fully flexible docking in the design of large combinatorial libraries. We have developed a fast structure-based screening
method, which utilizes docking of a limited number of compounds to build a 2D QSAR model used to rapidly score the rest of
the database. We compare here a model based on radial basis functions and a Bayesian categorization model. The number of compounds
that need to be actually docked depends on the number of docking hits found. In our case studies reasonable quality models
are built after docking of the number of molecules containing 50 docking hits. The rest of the library is screened by the
QSAR model. Optionally a fraction of the QSAR-prioritized library can be docked in order to find the true docking hits. The
quality of the model only depends on the training set size – not on the size of the library to be screened. Therefore, for
larger libraries the method yields higher gain in speed no change in performance. Prioritizing a large library with these
models provides a significant enrichment with docking hits: it attains the values of 13 and 35 at the beginning of the score-sorted
libraries in our two case studies: screening of the NCI collection and a combinatorial libraries on CDK2 kinase structure.
With such enrichments, only a fraction of the database must actually be docked to find many of the true hits. The throughput
of the method allows its use in screening of large compound collections and in the design of large combinatorial libraries.
The strategy proposed has an important effect on efficiency but does not affect retrieval of actives, the latter being determined
by the quality of the docking method itself.
Electronic supplementary material is available at http://dx.doi.org/10.1007/s10822-005-9002-6. 相似文献
9.
Nanjie Deng William F. Flynn Junchao Xia R. S. K. Vijayan Baofeng Zhang Peng He Ahmet Mentes Emilio Gallicchio Ronald M. Levy 《Journal of computer-aided molecular design》2016,30(9):743-751
We describe binding free energy calculations in the D3R Grand Challenge 2015 for blind prediction of the binding affinities of 180 ligands to Hsp90. The present D3R challenge was built around experimental datasets involving Heat shock protein (Hsp) 90, an ATP-dependent molecular chaperone which is an important anticancer drug target. The Hsp90 ATP binding site is known to be a challenging target for accurate calculations of ligand binding affinities because of the ligand-dependent conformational changes in the binding site, the presence of ordered waters and the broad chemical diversity of ligands that can bind at this site. Our primary focus here is to distinguish binders from nonbinders. Large scale absolute binding free energy calculations that cover over 3000 protein–ligand complexes were performed using the BEDAM method starting from docked structures generated by Glide docking. Although the ligand dataset in this study resembles an intermediate to late stage lead optimization project while the BEDAM method is mainly developed for early stage virtual screening of hit molecules, the BEDAM binding free energy scoring has resulted in a moderate enrichment of ligand screening against this challenging drug target. Results show that, using a statistical mechanics based free energy method like BEDAM starting from docked poses offers better enrichment than classical docking scoring functions and rescoring methods like Prime MM-GBSA for the Hsp90 data set in this blind challenge. Importantly, among the three methods tested here, only the mean value of the BEDAM binding free energy scores is able to separate the large group of binders from the small group of nonbinders with a gap of 2.4 kcal/mol. None of the three methods that we have tested provided accurate ranking of the affinities of the 147 active compounds. We discuss the possible sources of errors in the binding free energy calculations. The study suggests that BEDAM can be used strategically to discriminate binders from nonbinders in virtual screening and to more accurately predict the ligand binding modes prior to the more computationally expensive FEP calculations of binding affinity. 相似文献
10.
Matthew B. Gates Kenneth B. Tomer Leesa J. Deterding 《Journal of the American Society for Mass Spectrometry》2010,21(10):1649-1659
Several affinity resins consisting of ionic metals or metal oxides were investigated for their phosphopeptide enrichment capabilities
with subsequent mass spectrometric analyses. Commercially-available enrichment metal oxide affinity chromatography (MOAC)
resins using manufacturer’s and/or published protocols were compared and evaluated for the most efficient and selective method
that could be implemented as a standard enrichment procedure. From these comparative analyses, using a tryptic digest of casein
proteins, it was determined that in our hands, two of the resins out-performed the others based on a variety of criteria,
including the number of phosphorylation sites identified during MS analyses, the lower numbers of nonspecifically bound peptides
observed, and the limits of detection. Applicability of these enrichment resins to a complex biological mixture was investigated.
For this work, a mixture of avian histones was digested, subjected to titanium dioxide phosphopeptide enrichment, and analyzed
by mass spectrometry. Eight phosphorylated tryptic peptides were observed following enrichment and subsequent LC/MS/MS analyses.
Of note, seven of the eight phosphopeptides were not observed without titanium dioxide enrichment. From these analyses, four
sites of phosphorylation were unequivocally determined, two of which have not been reported previously. Four additional phosphopeptides
were observed; however, the site of phosphorylation could not be distinguished but was localized to one of two possible amino
acids. These methods should aid in the investigation of proteins post-translationally modified with phosphate, especially
those present at low concentrations as was demonstrated by successful enrichment at the femtomole level. 相似文献
11.
Zang Q Keire DA Wood RD Buhse LF Moore CM Nasr M Al-Hakim A Trehy ML Welsh WJ 《Analytical and bioanalytical chemistry》2011,399(2):635-649
Heparin, a widely used anticoagulant primarily extracted from animal sources, contains varying amounts of galactosamine impurities.
Currently, the United States Pharmacopeia (USP) monograph for heparin purity specifies that the weight percent of galactosamine
(%Gal) may not exceed 1%. In the present study, multivariate regression (MVR) analysis of 1H NMR spectral data obtained from heparin samples was employed to build quantitative models for the prediction of %Gal. MVR
analysis was conducted using four separate methods: multiple linear regression, ridge regression, partial least squares regression,
and support vector regression (SVR). Genetic algorithms and stepwise selection methods were applied for variable selection.
In each case, two separate prediction models were constructed: a global model based on dataset A which contained the full range (0–10%) of galactosamine in the samples and a local model based on the subset dataset B for which the galactosamine level (0–2%) spanned the 1% USP limit. All four regression
methods performed equally well for dataset A with low prediction errors under optimal conditions, whereas SVR was clearly
superior among the four methods for dataset B. The results from this study show that 1H NMR spectroscopy, already a USP requirement for the screening of contaminants in heparin, may offer utility as a rapid method
for quantitative determination of %Gal in heparin samples when used in conjunction with MVR approaches. 相似文献
12.
S Kawatkar D Moustakas M Miller D Joseph-McCarthy 《Journal of computer-aided molecular design》2012,26(8):921-934
An NMR fragment screening dataset with known binders and decoys was used to evaluate the ability of docking and re-scoring methods to identify fragment binders. Re-scoring docked poses using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) implicit solvent model identifies additional active fragments relative to either docking or random fragment screening alone. Early enrichment, which is clearly most important in practice for selecting relatively small sets of compounds for experimental testing, is improved by MM-PBSA re-scoring. In addition, the value in MM-PBSA re-scoring of docked poses for virtual screening may be in lessening the effect of the variation in the protein complex structure used. 相似文献
13.
A. Wucher J. Cheng L. Zheng N. Winograd 《Analytical and bioanalytical chemistry》2009,393(8):1835-1842
Molecular time of flight secondary ion mass spectrometry (ToF-SIMS) imaging and cluster ion beam erosion are combined to perform
a three-dimensional chemical analysis of molecular films. The resulting dataset allows a number of artifacts inherent in sputter
depth profiling to be assessed. These artifacts arise from lateral inhomogeneities of either the erosion rate or the sample
itself. Using a test structure based on a trehalose film deposited on Si, we demonstrate that the “local” depth resolution
may approach values which are close to the physical limit introduced by the information depth of the (static) ToF-SIMS method
itself. 相似文献
14.
SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges. 相似文献
15.
Jemma G. Kelly Plamen P. Angelov Júlio Trevisan Anastasia Vlachopoulou Evangelos Paraskevaidis Pierre L. Martin-Hirsch Francis L. Martin 《Analytical and bioanalytical chemistry》2010,398(5):2191-2201
Although the UK cervical screening programme has reduced mortality associated with invasive disease, advancement from a high-throughput
predictive methodology that is cost-effective and robust could greatly support the current system. We combined analysis by
attenuated total reflection Fourier-transform infrared spectroscopy of cervical cytology with self-learning classifier eClass.
This predictive algorithm can cope with vast amounts of multidimensional data with variable characteristics. Using a characterised
dataset [set A: consisting of UK cervical specimens designated as normal (n = 60), low-grade (n = 60) or high-grade (n = 60)] and one further dataset (set B) consisting of n = 30 low-grade samples, we set out to determine whether this approach could be robustly predictive. Variously extending the
training set consisting of set A with set B data produced good classification rates with three two-class cascade classifiers.
However, a single three-class classifier was equally efficient, producing a user-friendly, applicable methodology with improved
interpretability (i.e., better classification with only one set of fuzzy rules). As data from set B were added incrementally
to the training set, the model learned and evolved. Additionally, monitoring of results of the set B low-grade specimens (known
to be low-grade cervical cytology specimens) provided the opportunity to explore the possibility of distinguishing patients
likely to progress towards invasive disease. eClass exhibited a remarkably robust predictive power in a user-friendly fashion
(i.e., high throughput, ease of use) compared to other classifiers (k-nearest neighbours, support vector machines, artificial neural networks). Development of eClass to classify such datasets
for applications such as screening exhibits robustness in identifying a dichotomous marker of invasive disease progression. 相似文献
16.
Elisaveta K. Mladenova Ivanka G. Dakova Dimiter L. Tsalev Irina B. Karadjova 《Central European Journal of Chemistry》2012,10(4):1175-1182
A sorbent L-cysteine grafted silica gel has been evaluated for separation and enrichment of dissolved inorganic i-Hg(II) and methylmercury CH3Hg(I) from surface waters at sub-μg L−1 concentrations. Chemical parameters for mercury species enrichment and separation have been optimized. Analytical schemes for the determination of Hg species, using selective column solid phase extraction (SPE) with continuous flow chemical vapor generation atomic absorption spectrometry (CF-CVG-AAS) or inductively coupled plasma-mass spectrometry (ICP-MS) were developed. Possibilities for on-site SPE enrichment were demonstrated as well. The limits of quantification were 1.5 and 5 ng L−1 for dissolved i-Hg(II) and CH3Hg(I) by CF-CVG-AAS and 1 and 2.5 ng L−1 by ICP-MS with relative standard deviations between 7–12% and 7–14%, respectively. The chemically modified SPE sorbent has demonstrated high regeneration ability, chemical and mechanical stability, acceptable capacity and good enrichment factors. Results for total dissolved mercury were in reasonable agreement with those from independent analyses by direct ICP-MS determinations for river waters and for estuarine water certified reference material. 相似文献
17.
Fast multiresidue screening of 300 pesticides in water for human consumption by LC-MS/MS 总被引:1,自引:0,他引:1
The study tested the determination of 300 pesticides in mineral water at levels of 0.1 and 1.0 μg/L. Measurements were conducted
by direct sample injection into a liquid chromatograph coupled to a tandem mass spectrometer without any sample enrichment
and/or cleanup. Two separate injections enabled the recording of two transitions per analyte (600 selected reaction monitoring
transitions in total). For 285 analytes the sensitivity of direct sample injection (100 μL) was sufficient to quantify residues
at 0.1 μg/L. All remaining pesticides were detected at 1.0 μg/L. Calibration functions were linear for more than 80% of analytes.
Signal suppression or enhancement compared with signals in high-performance liquid chromatography water was equal to or smaller
than 20% for 240 analytes. Even the largest matrix-induced suppression did not result in the disappearance of peaks. Combining
the results of seven mineral waters, the relative standard deviation of “recovery” was 20% or less for 87% of the substances.
A second transition for confirmatory purposes was often available. Consequently, the proposed direct injection of samples
without any sample enrichment and/or cleanup is suitable for screening of many pesticides in mineral and drinking water. 相似文献
18.
Graham SF Ruiz-Aracama A Lommen A Cannizzo FT Biolatti B Elliott CT Mooney MH 《Analytical and bioanalytical chemistry》2012,403(2):573-582
Detection of growth-promoter use in animal production systems still proves to be an analytical challenge despite years of
activity in the field. This study reports on the capability of NMR metabolomic profiling techniques to discriminate between
plasma samples obtained from cattle treated with different groups of growth-promoting hormones (dexamethasone, prednisolone,
oestradiol) based on recorded metabolite profiles. Two methods of NMR analysis were investigated—a Carr–Purcell–Meiboom–Gill
(CPMG)-pulse sequence technique and a conventional 1H NMR method using pre-extracted plasma. Using the CPMG method, 17 distinct metabolites could be identified from the spectra.
1H NMR analysis of extracted plasma facilitated identification of 23 metabolites—six more than the alternative method and all
within the aromatic region. Multivariate statistical analysis of acquired data from both forms of NMR analysis separated the
plasma metabolite profiles into distinct sample cluster sets representative of the different animal study groups. Samples
from both sets of corticosteroid-treated animals—dexamethasone and prednisolone—were found to be clustered relatively closely
and had similar alterations to identified metabolite panels. Distinctive metabolite profiles, different from those observed
within plasma from corticosteroid-treated animal plasma, were observed in oestradiol-treated animals and samples from these
animals formed a cluster spatially isolated from control animal plasma samples. These findings suggest the potential use of
NMR methodologies of plasma metabolite analysis as a high-throughput screening technique to aid detection of growth promoter
use. 相似文献
19.
In this work, we compared the use of repeated cycles of centrifugation at conventional speeds for enrichment of exosomes from human serum compared to the use of ultracentrifugation (UC). After removal of cells and cell debris, a speed of 110 000 × g or 40 000 × g was used for the UC or centrifugation enrichment process, respectively. The enriched exosomes were analyzed using the bicinchoninic acid assay, 1D gel separation, transmission electron microscopy, Western blotting, and high‐resolution LC‐MS/MS analysis. It was found that a five‐cycle repetition of UC or centrifugation is necessary for successful removal of nonexosomal proteins in the enrichment of exosomes from human serum. More significantly, 5× centrifugation enrichment was found to provide similar or better performance than 5× UC enrichment in terms of enriched exosome protein amount, Western blot band intensity for detection of CD‐63, and numbers of identified exosome‐related proteins and cluster of differentiation (CD) proteins. A total of 478 proteins were identified in the LC‐MS/MS analyses of exosome proteins obtained from 5× UCs and 5× centrifugations including many important CD membrane proteins. The presence of previously reported exosome‐related proteins including key exosome protein markers demonstrates the utility of this method for analysis of proteins in human serum. 相似文献
20.
Virtual screening has become a popular tool to identify novel leads in the early phases of drug discovery. A variety of docking
and scoring methods used in virtual screening have been the subject of active research in an effort to gauge limitations and
articulate best practices. However, how to best utilize different scoring functions and various crystal structures, when available,
is not yet well understood. In this work we use multiple crystal structures of PI3 K-γ in both prospective and retrospective
virtual screening experiments. Both Glide SP scoring and Prime MM-GBSA rescoring are utilized in the prospective and retrospective
virtual screens, and consensus scoring is investigated in the retrospective virtual screening experiments. The results show
that each of the different crystal structures that was used, samples a different chemical space, i.e. different chemotypes
are prioritized by each structure. In addition, the different (re)scoring functions prioritize different chemotypes as well.
Somewhat surprisingly, the Prime MM-GBSA scoring function generally gives lower enrichments than Glide SP. Finally we investigate
the impact of different ligand preparation protocols on virtual screening enrichment factors. In summary, different crystal
structures and different scoring functions are complementary to each other and allow for a wider variety of chemotypes to
be considered for experimental follow-up. 相似文献