1,355,212 research outputs found
Principles of QSAR Modeling
No full textAt the end of her academic career, the author summarizes the main aspects of QSAR modeling, giving comments and suggestions according to her 23 years’ experience in QSAR research on environmental topics. The focus is mainly on Multiple Linear Regression, particularly Ordinary Least Squares, using a Genetic Algorithm for variable selection from various theoretical molecular descriptors, but
the comments can be useful also for other QSAR methods. The need for rigorous validation, also external, and for applicability domain check to guarantee predictivity and reliability of QSAR models is particularly highlighted. The commented approach is the “predictive” one, based on chemometrics, and is usefully applied to the prioritization of environmental pollutants. All the discussed points and
the author’s ideas are implemented in the software QSARINS, as a legacy to the QSAR community
PBT assessment and prioritization of Contaminants of Emerging Concern: Pharmaceuticals
No full textThe strong and widespread use of pharmaceuticals, together with incorrect disposal procedures, has recently made these products contaminants of emerging concern (CEC). Unfortunately, little is known about pharmaceuticals' environmental behaviour and ecotoxicity, so that EMEA (European Medicines Agency) released guidelines for the pharmaceuticals' environmental risk assessment. In particular, there is a severe lack of information about persistence, bioaccumulation and toxicity (PBT) of the majority of the thousands of substances on the market. Computational tools, like QSAR (Quantitative Structure Activity Relationship) models, are the only way to screen large sets of chemicals in short time, with the aim of ranking, highlighting and prioritizing the most environmentally hazardous for focusing further experimental studies.
In this work we propose a screening method to assess the potential persistence, bioaccumulation and toxicity of more than 1200 pharmaceutical ingredients, based on the application of two different QSAR models. We applied the Insubria-PBT Index, a MLR (Multiple Linear Regression) QSAR model based on four simple molecular descriptors, implemented in QSARINS software, and able to synthesize the PBT potential in a unique cumulative value and the US-EPA PBT Profiler that assesses the PBT behaviour evaluating separately P, B and T. Particular attention was given to the study of Applicability Domain in order to provide reliable predictions. An agreement of 86% was found between the two models and a priority list of 35 pharmaceuticals, highlighted as potential PBTs by consensus, was proposed for further experimental validation. Moreover, the results of this computational screening are in agreement with preliminary experimental data in the literature. This study shows how in silico models can be applied in the hazard assessment to perform preliminary screening and prioritization of chemicals, and how the identification of the structural features, mainly associated with the potential PBT behaviour of the prioritized pharmaceuticals, is particularly relevant to perform the rational a priori design of new, environmentally safer, pharmaceuticals
WHIM descriptors of shape
No full textWHIM descriptors are 3D structural descriptors obtained from the (x,y,z)-atomic coordinates of a molecular conformation of a chemical, and are used successfully in QSAR modelling. They are built in so as to capture relevant 3D information regarding different features of molecular structure: size, shape, symmetry and atom distribution.
Different weights are used to obtain particular information for each set of descriptors.
Recently, some doubts have been raised in the literature regarding the ability of Weighted
Holistic Invariant Molecular (WHIM) descriptors of shape (the K non-directional WHIM descriptors) to describe the difference between linear and non-linear molecules. A data set of seventy aliphatic and aromatic chemicals of different shape (linear and branched
congeners) has been studied here, and is represented by K descriptors (global nondirectional WHIM descriptors of shape) based on different weights. The K descriptors range from 0 for a spherical molecule to 1 for a perfectly linear molecule. The present
study confirms the findings, already reported by the author, that the WHIM descriptors of shape (K) are unequivocally able to differentiate linear and non-linear molecules
Principles of QSAR models validation: internal and external
No full textThe recent REACH Policy of the European Union has led to scientists and regulators to focus their attention on establishing general validation principles for QSAR models in the context of chemical regulation (previously known as the Setubal, nowadays, the OECD principles). This paper gives a brief analysis of some principles: unambiguous algorithm, Applicability Domain (AD), and statistical validation. Some concerns related to QSAR
algorithm reproducibility and an example of a fast check of the applicability domain for MLR models are presented. Common myths and misconceptions related to popular techniques for verifying internal predictivity, particularly for MLR models (for instance crossvalidation,
bootstrap), are commented on and compared with commonly used statistical techniques for external validation. The differences in the two validating approaches are highlighted, and evidence is presented that only models that have been validated externally, after their internal validation, can be considered reliable and applicable for both external prediction and regulatory purposes.
(“Validation is one of those words...that is constantly used and seldom defined” as stated by A. R. Feinstein in the book Multivariate Analysis: An Introduction, Yale University Press, New Haven, 1996)
Review. Ştefan Găitănaru, Gramatica critică a limbii române, Editura Universităţii din Piteşti, Piteşti, 2018, 468 p.
No full textŞTEFAN GĂITĂNARU, Gramatica critică a limbii române, Pitești, 2018.
This is a review of a work which aims at critically analysing the grammatical codification of the Romanian language in the latest academic treatises (GALR, 2000/2006; GBLR. 2005/2010). Ștefan Găitănaru, the author of the Gramatica critică a limbii române, române (‘The Critical Grammar of the Romanian Language’), published by the University of Pitești, examines the arguments for various innovations in the interpretation of language facts, proposing counterarguments and providing his own interpretations related to them
Predictive QSAR modelling for Screening and Prioritization of Environmental Organic Pollutants
No full textQSAR models are mainly useful in the prediction of data for chemicals without experimental information, those not yet tested or even not yet synthesized. However, QSAR models must be carefully verified for their reliability in the specific context of application to be successfully used and not misused. The OECD principles for QSAR model validation have established crucial points for prediction reliability, mainly model reproducibility, external predictivity and applicability domain checking. Particular attention must be paid to QSAR models’ predictive performance, when the models are applied to the screening of large chemical sets, the specific aim being to focus on the most hazardous to prioritize them for experimental tests. Different approaches for splitting the available experimental data sets and various statistical parameters can be used to verify a model’s external predictivity. These fundamental aspects of QSAR model reliability are commented on, based on several examples of application to various environmental organic pollutants, such as Persistent, Bioaccumulative and Toxic (PBTs) chemicals, Endocrine Disruptors (EDs), flame retardants and polyfluorinated chemicals. Some of these compounds are included in the priority list of Persistent Organic Pollutants (POPs) and/or are among the substances of very high concern (SVHCs), which require authorization in REACH. Therefore methods are needed for an early identification of these pollutants. The QSAR models presented could be particularly useful for screening and prioritisation purposes, also a priori in a green chemistry approach, in the design of new products as safer alternatives to existing dangerous chemicals (“benign by design”)
La Gramatica de la Lengua Vulgar de España (Lovaina, 1559) ¿anónima?
No full textPara demostrar la autoría de la Gramatica de la Lengua Vulgar de España nos basamos en los siguientes puntos: el uso en El Concejo i Consejeros del Príncipe (Amberes, 1559) de Furio Ceriol de las normas ortográficas propuestas en la Gramatica; la denominación de la lengua castellana o española como lengua 'vulgar' de España, en la misma obra de Ceriol; las ideas lingüísticas contenidas en la Gramatica y en Bononia de Ceriol; la organización retórica de la Gramatica; y, en último lugar, la comparación entre el poema dedicatorio en la Gramatica y los de las obras de Furio Ceriol
Introduction to the need of Alternative Methods in REACH
No full textIn vitro and in silico methods are foreseen in the EU regulation REACH, to prioritize more dangerous compounds, to focus expensive experiments, by reducing animal tests and to fill the data gaps. A brief historical introduction of QSAR modelling and the importance of model validation according to the OECD principles for reliable predictions is presented
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