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PubMed | U.S. Food and Drug Administration, University of Maryland University College, U.S. Department of Agriculture, Zhejiang University of Technology and ACD Labs Inc.
Type: | Journal: Magnetic resonance in chemistry : MRC | Year: 2016

The structure of a novel compound from Adansonia digitata has been elucidated, and its

Burgers P.C.,Erasmus Medical Center | McGibbon G.A.,ACD Labs Inc. | Jobst K.J.,McMaster University | Jobst K.J.,Environment Canada
European Journal of Mass Spectrometry | Year: 2012

Early combined computational and experimental studies by J.K. Terlouw and colleagues propose that low-energy methyl carbamate ions, NH 2COOCH 3 •+ (MC-1), rearrange into distonic ions NH 2C(OH)OCH 2 •+ and hydrogen-bridged radical cations [NH 2C=O-H-OCH 2] •+ (MC-5) en route to the observed losses of HCO • and CO. In this study, we report on the generation of ions MC-5 by decarbonylation of ionized methyl oxamate NH 2COCOOCH 3 •+. Theory and experiment agree that ion MC-5 is a key intermediate in the dissociation of low-energy ions MC-1. The subsequent HCO • loss, however, may not proceed via the route proposed by Terlouw et al., but rather by an entirely different mechanism involving proton-transport catalysis (PTC) in ion MC-5. This view is further supported by the dissociation behaviour of the MC-5 isotopologue [ND 2C=O-D-OCH 2] •+, which is conveniently generated from the d 3-labelled glycolamide ion DOCH 2C(=O)ND 2 •+ © IM Publications LLP 2012 All rights reserved.

Ovenden S.P.B.,Defence Science and Technology Organisation, Australia | Nielson J.L.,ACD Labs Inc. | Liptrot C.H.,James Cook University | Willis R.H.,Australian Institute of Marine Science | And 3 more authors.
Molecules | Year: 2012

The methanol extract of an assemblage of Halimeda stuposa and a Dictyota sp., yielded three natural products characteristic of Dictyota sp., and one of Halimeda sp. These included the xenicane diterpene 4-hydroxydictyolactone (1), and the diterpenes dictyol E (2), 8a,11-dihydroxypachydictyol A (3) and indole-3-carboxaldehyde (4). A minor revision of 1 and new spectroscopic data for 1 and 2 are provided, along with associated anti-cancer activities of compounds 1-4. © 2012 by the authors.

PubMed | Hichrom Ltd, ACD Labs Inc. and Novo Nordisk AS
Type: Journal Article | Journal: Analytical and bioanalytical chemistry | Year: 2015

The retention behaviour of acidic, basic and quaternary ammonium salts and polar neutral analytes has been evaluated on acidic, basic and neutral hydrophilic interaction chromatography (HILIC) stationary phases as a function of HILIC operating parameters such as MeCN content, buffer concentration, pH and temperature. Numerous empirical HILIC retention models (existing and newly developed ones) have been assessed for their ability to describe retention as a function of the HILIC operating parameters investigated. Retention models have been incorporated into a commercially available retention modelling programme (i.e. ACD/LC simulator) and their accuracy of retention prediction assessed. The applicability of HILIC modelling using these equations has been demonstrated in the two-dimensional isocratic (i.e. buffer concentration versus MeCN content modelling) and one-dimensional gradient separations for a range of analytes of differing physico-chemical properties on the three stationary phases. The accuracy of retention and peak width prediction was observed to be comparable to that reported in reversed-phase chromatography (RPC) retention modelling. Intriguingly, our results have confirmed that the use of gradient modelling to predict HILIC isocratic conditions and vice versa is not reliable. A relative ranking of the importance of the retention and selectivity of HILIC operating parameters has been determined using statistical approaches. For retention, the order of importance was observed to be organic content>stationary phase>temperaturemobile phase pH (i.e. pH 3-6 which mainly effects the ionization of the analyte)buffer concentration. For selectivity, the nature of the stationary phase>mobile phase pH>buffer concentration>temperature>organic content.

Didziapetris R.,VsI Aukstieji algoritmai | Didziapetris R.,ACD Labs Inc. | Lanevskij K.,VsI Aukstieji algoritmai | Lanevskij K.,ACD Labs Inc.
Journal of Computer-Aided Molecular Design | Year: 2016

A large and chemically diverse hERG inhibition data set comprised of 6690 compounds was constructed on the basis of ChEMBL bioactivity database and original publications dealing with experimental determination of hERG activities using patch-clamp and competitive displacement assays. The collected data were converted to binary format at 10 µM activity threshold and subjected to gradient boosting machine classification analysis using a minimal set of physicochemical and topological descriptors. The tested parameters involved lipophilicity (log P), ionization (pKa), polar surface area, aromaticity, molecular size and flexibility. The employed approach allowed classifying the compounds with an overall 75–80 % accuracy, even though it only accounted for non-specific interactions between hERG and ligand molecules. The observed descriptor-response profiles were consistent with common knowledge about hERG ligand binding site, but also revealed several important quantitative trends, as well as slight inter-assay variability in hERG inhibition data. The results suggest that even weakly basic groups (pKa < 6) might substantially contribute to hERG inhibition potential, whereas the role of lipophilicity depends on the compound’s ionization state, and the influence of log P decreases in the order of bases > zwitterions > neutrals > acids. Given its robust performance and clear physicochemical interpretation, the proposed model may provide valuable information to direct drug discovery efforts towards compounds with reduced risk of hERG-related cardiotoxicity. © 2016 Springer International Publishing Switzerland

Antler M.,ACD Labs Inc.
Reading for the R and D Community | Year: 2010

Mass spectrometry (MS) instrument vendors offer automated MS/MS data collection for analytes that are present above a certain intensity threshold, or for expected metabolites. ACD/Labs have developed ACD/Metabolite ID Suite™ that generates a report of retention times, peak areas, and spectra for each expected metabolite. Additional software modules can predict metabolite structures for a new drug, identifying the sites most likely to be susceptible to metabolism by human liver microsomes, which can help with both structure elucidation and drug design. The ACD/Metabolite ID Suite™ can help extract the likely metabolite peaks from a complex full-scan liquid chromatography-mass chromatography (LC/MS) data set. The software can compare the metabolized sample with a control sample and identify unique features in the metabolized sample. Software reduces the complex data set to a short list of peaks for further review, interprets the spectrum to determine the mass of the protonated molecule, and determines potential chemical formulae for the potential metabolite.

Sazonovas A.,ACD Labs Inc. | Sazonovas A.,Vilnius University | Japertas P.,ACD Labs Inc. | Didziapetris R.,ACD Labs Inc.
SAR and QSAR in Environmental Research | Year: 2010

This study presents a new type of acute toxicity (LD50) prediction that enables automated assessment of the reliability of predictions (which is synonymous with the assessment of the Model Applicability Domain as defined by the Organization for Economic Cooperation and Development). Analysis involved nearly 75,000 compounds from six animal systems (acute rat toxicity after oral and intraperitoneal administration; acute mouse toxicity after oral, intraperitoneal, intravenous, and subcutaneous administration). Fragmental Partial Least Squares (PLS) with 100 bootstraps yielded baseline predictions that were automatically corrected for non-linear effects in local chemical spaces-a combination called Global, Adjusted Locally According to Similarity (GALAS) modelling methodology. Each prediction obtained in this manner is provided with a reliability index value that depends on both compound's similarity to the training set (that accounts for similar trends in LD50 variations within multiple bootstraps) and consistency of experimental results with regard to the baseline model in the local chemical environment. The actual performance of the Reliability Index (RI) was proven by its good (and uniform) correlations with Root Mean Square Error (RMSE) in all validation sets, thus providing quantitative assessment of the Model Applicability Domain. The obtained models can be used for compound screening in the early stages of drug development and prioritization for experimental in vitro testing or later in vivo animal acute toxicity studies. © 2010 Taylor & Francis.

Didziapetris R.,ACD Labs Inc. | Dapkunas J.,ACD Labs Inc. | Sazonovas A.,ACD Labs Inc. | Japertas P.,ACD Labs Inc.
Journal of Computer-Aided Molecular Design | Year: 2010

A new structure-activity relationship model predicting the probability for a compound to inhibit human cytochrome P450 3A4 has been developed using data for >800 compounds from various literature sources and tested on PubChem screening data. Novel GALAS (Global, Adjusted Locally According to Similarity) modeling methodology has been used, which is a combination of baseline global QSAR model and local similarity based corrections. GALAS modeling method allows forecasting the reliability of prediction thus defining the model applicability domain. For compounds within this domain the statistical results of the final model approach the data consistency between experimental data from literature and PubChem datasets with the overall accuracy of 89%. However, the original model is applicable only for less than a half of PubChem database. Since the similarity correction procedure of GALAS modeling method allows straightforward model training, the possibility to expand the applicability domain has been investigated. Experimental data from PubChem dataset served as an example of in-house high-throughput screening data. The model successfully adapted itself to both data classified using the same and different IC50 threshold compared with the training set. In addition, adjustment of the CYP3A4 inhibition model to compounds with a novel chemical scaffold has been demonstrated. The reported GALAS model is proposed as a useful tool for virtual screening of compounds for possible drug-drug interactions even prior to the actual synthesis. © 2010 Springer Science+Business Media B.V.

Samokhin A.,Moscow State University | Sotnezova K.,Moscow State University | Lashin V.,ACD Labs Inc. | Revelsky I.,Moscow State University
Journal of Mass Spectrometry | Year: 2015

Performance of several library search algorithms (against EI mass spectral databases) implemented in commercial software products (acd/specdb, chemstation, gc/ms solution and ms search) was estimated. Test set contained 1000 mass spectra, which were randomly selected from NIST'08 (RepLib) mass spectral database. It was shown that composite (also known as identity) algorithm implemented in ms search (NIST) software gives statistically the best results: the correct compound occupied the first position in the list of possible candidates in 81% of cases; the correct compound was within the list of top ten candidates in 98% of cases. It was found that use of presearch option can lead to rejection of the correct answer from the list of possible candidates (therefore presearch option should not be used, if possible). Overall performance of library search algorithms was estimated using receiver operating characteristic curves. © 2015 John Wiley & Sons, Ltd.

Pletnev I.,FIZ CHEMIE Berlin | Erin A.,ACD Labs Inc. | McNaught A.,U.S. National Institute of Standards and Technology | Blinov K.,ACD Labs Inc. | And 2 more authors.
Journal of Cheminformatics | Year: 2012

InChIKey is a 27-character compacted (hashed) version of InChI which is intended for Internet and database searching/indexing and is based on an SHA-256 hash of the InChI character string. The first block of InChIKey encodes molecular skeleton while the second block represents various kinds of isomerism (stereo, tautomeric, etc.). InChIKey is designed to be a nearly unique substitute for the parent InChI. However, a single InChIKey may occasionally map to two or more InChI strings (collision). The appearance of collision itself does not compromise the signature as collision-free hashing is impossible; the only viable approach is to set and keep a reasonable level of collision resistance which is sufficient for typical applications. © 2012 Bachrach; licensee Chemistry Central Ltd.

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