Structural and Physico-Chemical Interpretation (SPCI) of QSAR Models and Its Comparison with Matched Molecular Pair Analysis

Polishchuk, Pavel; Tinkov, O V; Khristova, T.M.; Ognichenko, L. N.; Kosinskaya, A. P.; Varnek, Alexandre; Кузьмин, В. Е.

doi:10.1021/acs.jcim.6b00371

Cited by 41 publications

(54 citation statements)

References 57 publications

(79 reference statements)

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“…In the case of ANN, the method consists of nonlinear multivariate statistics, dealing with compounds that can act by different mechanisms of action. These nonlinear methods are considered a gold standard due to their high predictive ability in these cases [43]. Thus, we found an ANN able to predict antitrypanosomatid activities ( R 2 > 0.75, Q 2 > 0.62, and P 2 > 0.67; Table 2; Figure S1) and TEAC (Table 2, Figure S1), but not the cytotoxic activity in L6 cells ( R 2 = 0.63, Q 2 < 0.5, and P 2 < 0.5; Table 2; Figure S1).…”

Section: Resultsmentioning

confidence: 99%

The Correlation between Chemical Structures and Antioxidant, Prooxidant, and Antitrypanosomatid Properties of Flavonoids

Baldim

Alcântara

Domingos

et al. 2017

Oxidative Medicine and Cellular Longevity

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Flavonoids have demonstrated in vivo and in vitro leishmanicidal, trypanocidal, antioxidant, and prooxidant properties. The chemotherapy of trypanosomiasis and leishmaniasis lacks efficacy, presents high toxicity, and is related to the development of drug resistance. Thus, a series of 40 flavonoids were investigated with the purpose of correlating these properties via structure and activity analyses based on integrated networks and QSAR models. The classical groups for the antioxidant activity of flavonoids were combined in order to explain the influence of antioxidant and prooxidant activities on the antiparasitic properties. These analyses become useful for the development of efficient treatments for leishmaniasis and trypanosomiasis. Finally, the dual activity of flavonoids presenting both anti- and prooxidant activities revealed that the existence of a balance between these two features could be important to the development of adequate therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

The Correlation between Chemical Structures and Antioxidant, Prooxidant, and Antitrypanosomatid Properties of Flavonoids

Baldim

Alcântara

Domingos

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…The curated data set comprised 1984 compounds whose structures and activity values are provided in Supplementary materials. All modelling steps including descriptor calculation, model development and validation, molecule fragmentation and calculation of fragment contributions were performed with the open‐source spci software ,…”

Section: Methodsmentioning

confidence: 99%

“…Descriptors were calculated by the sirms tool included in the spci software . More details about descriptor calculation are available in previous publications ,…”

Section: Methodsmentioning

confidence: 99%

“…They allow for the calculation of the contributions of single atoms, arbitrary fragments, or predicted activity changes corresponding to given molecular transformations . The contributions of identical fragments/transformations are usually averaged to reveal general trends in structure‐property relationships . Whilst useful, currently none of these approaches take into account the molecular context of the fragments considered which may significantly influence the fragment's behavior, e. g. transforming a “safe” non‐toxicophoric moiety into a reactive group.…”

Section: Introductionmentioning

confidence: 99%

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Interpretation of QSAR Models: Mining Structural Patterns Taking into Account Molecular Context

Matveieva

Cronin

Polishchuk

2018

Molecular Informatics

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The study focused on QSAR model interpretation. The goal was to develop a workflow for the identification of molecular fragments in different contexts important for the property modelled. Using a previously established approach -Structural and physicochemical interpretation of QSAR models (SPCI) -fragment contributions were calculated and their relative influence on the compounds' properties characterised. Analysis of the distributions of these contributions using Gaussian mixture modelling was performed to identify groups of compounds (clusters) comprising the same fragment, where these fragments had substantially different contributions to the property studied. SMARTSminer was used to detect patterns discriminating groups of compounds from each other and visual inspection if the former did not help. The approach was applied to analyse the toxicity, in terms of 40 hour inhibition of growth, of 1984 compounds to Tetrahymena pyriformis. The results showed that the clustering technique correctly identified known toxicophoric patterns: it detected groups of compounds where fragments have specific molecular context making them contribute substantially more to toxicity. The results show the applicability of the interpretation of QSAR models to retrieve reasonable patterns, even from data sets consisting of compounds having different mechanisms of action, something which is difficult to achieve using conventional pattern/data mining approaches.

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“…Golmohammadi et al, 2017), partial least square (PLS; (Cuadrado et al, 2007) and random forest analysis (RFA) (e.g. (Polishchuk et al, 2016). In the field of machine learning, the computer has the ability to "learn" from data (i.e.…”

Section: Models On Blood-brain-barrier (Bbb) Permeation and Neurotoximentioning

confidence: 99%

Literature review and appraisal on alternative neurotoxicity testing methods

Masjosthusmann

Barenys

El‐Gamal

et al. 2018

EFSA Supporting Publications

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The goal of this review was the evaluation of information on assessment methods in the field of alternative neurotoxicity (NT) testing. We therefore performed a systematic and comprehensive collection of scientific literature (in English) from the past 27 years until mid of 2017 on state of the art alternative testing methods including in vitro test methods, in silico methods and alternative non-mammalian models. This review identified a variety of test methods that have the ability to predict NT of chemicals based on predefined key NT endpoint categories (27). Those endpoint categories were derived from the Mode of Action (MoA) of known human neurotoxicants. Pre-evaluated MoAs of human neurotoxicants allowed the identification of performance characteristics with regard to the ability of a test system to correctly predict a chemical effect on an endpoint category. The most predictive in vitro model that covers a large variety of endpoint categories are primary rodent cells or tissues. Human based systems derived from induced pluripotent stem cells (iPSC) are promising and warrant human relevance. There is however not yet sufficient data on these models to demonstrate their suitability to reliably substitute primary rodent cells for NT testing purposes. Test methods for glia toxicity are rare and glia endpoint categories are clearly underrepresented. Therefore, a focus for future method development should be placed on glia, astrocytes, oligodendrocytes and microglia based models, preferably in a co-culture se up. The review on in silico methods, resulted into 54 QSARs publications, relevant for NT, of which 39 on blood brain barrier (BBB) permeation. The QSARs available in the publications were developed from data on drugs and chemicals, but there appears a limited set of experimental data for chemicals and pesticides on blood-brain barrier passage. The evaluation of NT methods using alternative whole organism approaches demonstrated a majority of data for C. elegans (nematode species), represented with high true prediction (96%). The main endpoint category was inhibition of cholinergic transmission, with specific endpoints for AChE activity and motor activity, the latter confirming the added value of a whole organism approach among alternative models. Though D. rerio, the zebrafish model appeared a www.efsa.europa.eu/publications 2 EFSA Supporting publication 2018:EN-1410The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights ...

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Structural and Physico-Chemical Interpretation (SPCI) of QSAR Models and Its Comparison with Matched Molecular Pair Analysis

Cited by 41 publications

References 57 publications

The Correlation between Chemical Structures and Antioxidant, Prooxidant, and Antitrypanosomatid Properties of Flavonoids

The Correlation between Chemical Structures and Antioxidant, Prooxidant, and Antitrypanosomatid Properties of Flavonoids

Interpretation of QSAR Models: Mining Structural Patterns Taking into Account Molecular Context

Literature review and appraisal on alternative neurotoxicity testing methods

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