Conformation-dependent QSAR approach for the prediction of inhibitory activity of bromodomain modulators

<p>Epigenetic drug discovery is a promising research field with growing interest in the scientific community, as evidenced by the number of publications and the large amount of structure-epigenetic activity information currently available in the public domain. Computational methods are valuable tools to analyse and understand the activity of large compound collections from their structural information. In this manuscript, QSAR models to predict the inhibitory activity of a diverse and heterogeneous set of 88 organic molecules against the bromodomains BRD2, BRD3 and BRD4 are presented. A conformation-dependent representation of the chemical structures was established using the RDKit software and a training and test set division was performed. Several two-linear and three-linear QuBiLS-MIDAS molecular descriptors (<a href="http://www.tomocomd.com" target="_blank">www.tomocomd.com</a>) were computed to extract the geometric structural features of the compounds studied. QuBiLS-MIDAS-based features sets, to be used in the modelling, were selected using dimensionality reduction strategies. The multiple linear regression procedure coupled with a genetic algorithm were employed to build the predictive models. Regression models containing between 6 to 9 variables were developed and assessed according to several internal and external validation methods. Analyses of outlier compounds and the applicability domain for each model were performed. As a result, the models against BRD2 and BRD3 with 8 variables and the model with 9 variables against BRD4 were those with the best overall performance according to the criteria accounted for. The results obtained suggest that the models proposed will be a good tool for studying the inhibitory activities of drug candidates against the bromodomains considered during epigenetic drug discovery.</p

First record of the alien pest Rhaponticum repens (Compositae) in the Iberian Peninsula

First record of the alien pest Rhaponticum repens (Compositae) in the Iberian Peninsula.- Rhaponticum repens is reported for the first time for the flora of the Iberian Peninsula. The species is native from Central Asia and has become invasive in Argentina, Canada, Europe and the USA. It was detected for the first time in abandoned fields from Vilablareix, near the city of Girona (Catalonia, Spain) and in the valley of the Vinalopó in Alicante (Valencia, Spain), where it was collected as early as in 1959 but misdentified. Molecular data, based on nrDNA region ITS, suggest that the reported populations may be closely related to plants from the United States. Due to the extremely noxious character of the species and the possible relationship of Spanish plants with the invasive American populations, some kind of monitoring is recommended.Rhaponticum repens (Compositae), una nueva planta alóctona para la Península Ibérica.- Se cita por primera vez la especie Rhaponticum repens para la flora de la Península Ibérica. Rhaponticum repens es una especie nativa de Asia central que actúa como invasora en diversos países como Argentina, Canadá o los Estados Unidos. Se ha encontrado por primera vez en campos de cultivo abandonados en el pueblo de Vilablareix, cerca de la ciudad de Girona (Cataluña, España) y en el valle del Vinalopó (Valencia, España), donde fue recolectada y mal identificada en 1959. Los datos moleculares, obtenidos a partir de la región ITS del nrDNA, sugieren que estas poblaciones podrían estar relacionadas con plantas invasoras de Estados Unidos. Debido al carácter extremadamente invasor de la especie, y a su posible origen secundario a partir de las poblaciones norteamericanas, se recomienda el seguimiento de estas poblacione

<i>N</i>-tuple topological/geometric cutoffs for 3D <i>N</i>-linear algebraic molecular codifications: variability, linear independence and QSAR analysis

<p>Novel <i>N</i>-tuple topological/geometric cutoffs to consider specific inter-atomic relations in the QuBiLS-MIDAS framework are introduced in this manuscript. These molecular cutoffs permit the taking into account of relations between more than two atoms by using (dis-)similarity multi-metrics and the concepts related with topological and Euclidean-geometric distances. To this end, the <i>k</i>th two-, three- and four-tuple topological and geometric neighbourhood quotient (NQ) total (or local-fragment) spatial-(dis)similarity matrices are defined, to represent 3D information corresponding to the relations between two, three and four atoms of the molecular structures that satisfy certain cutoff criteria. First, an analysis of a diverse chemical space for the most common values of topological/Euclidean-geometric distances, bond/dihedral angles, triangle/quadrilateral perimeters, triangle area and volume was performed in order to determine the intervals to take into account in the cutoff procedures. A variability analysis based on Shannon’s entropy reveals that better distribution patterns are attained with the descriptors based on the cutoffs proposed (QuBiLS-MIDAS NQ-MDs) with regard to the results obtained when all inter-atomic relations are considered (QuBiLS-MIDAS KA-MDs – ‘Keep All’). A principal component analysis shows that the novel molecular cutoffs codify chemical information captured by the respective QuBiLS-MIDAS KA-MDs, as well as information not captured by the latter. Lastly, a QSAR study to obtain deeper knowledge of the contribution of the proposed methods was carried out, using four molecular datasets (steroids (STER), angiotensin converting enzyme (ACE), thermolysin inhibitors (THER) and thrombin inhibitors (THR)) widely used as benchmarks in the evaluation of several methodologies. One to four variable QSAR models based on multiple linear regression were developed for each compound dataset following the original division into training and test sets. The results obtained reveal that the novel cutoff procedures yield superior performances relative to those of the QuBiLS-MIDAS KA-MDs in the prediction of the biological activities considered. From the results achieved, it can be suggested that the proposed <i>N</i>-tuple topological/geometric cutoffs constitute a relevant criteria for generating MDs codifying particular atomic relations, ultimately useful in enhancing the modelling capacity of the QuBiLS-MIDAS 3D-MDs.</p

Tensor algebra-based geometric methodology to codify central chirality on organic molecules

<p>A novel mathematical procedure to codify chiral features of organic molecules in the QuBiLS-MIDAS framework is introduced. This procedure constitutes a generalization to that commonly used to date, where the values 1 and −1 (correction factor) are employed to weight the molecular vectors when each atom is labelled as R (<i>rectus</i>) or S (<i>sinister</i>) according to the Cahn–Ingold–Prelog rules. Therefore, values in the range with steps equal to 0.25 may be accounted for. The atoms labelled R or S can have negative and positive values assigned (e.g. −3 for an R atom and 1 for an S atom, or vice versa), opposed values (e.g. −3 for an R atom and 3 for an S atom, or vice versa), positive values (e.g. 3 for an R atom and 1 for an S atom) or negative values (e.g. −3 for an R atom and −1 for an S atom). These proposed Chiral QuBiLS-MIDAS 3D-MDs are real numbers, non-symmetric and reduced to ‘classical’ (non-chiral) QuBiLS-MIDAS 3D-MDs when symmetry is not codified (correction factor equal to zero). In this report, only the factors with opposed values were considered with the purpose of demonstrating the feasibility of this proposal. From QSAR modelling carried out on four chemical datasets (Cramer’s steroids, fenoterol stereoisomer derivatives, <i>N</i>-alkylated 3-(3-hydroxyphenyl)-piperidines, and perindoprilat stereoisomers), it was demonstrated that the use of several correction factors contributes to the building of models with greater robustness and predictive ability than those reported in the literature, as well as with respect to the models exclusively developed with QuBiLS-MIDAS 3D-MDs based on the factor 1 | −1. In conclusion, it can be stated that this novel strategy constitutes a suitable alternative to computed chirality-based descriptors, contributing to the development of good models to predict properties depending on symmetry.</p

Drug repositioning for novel antitrichomonas from known antiprotozoan drugs using hierarchical screening

Aim: Metronidazole is the most widely used drug in trichomoniasis therapy. However, the emergence of metronidazole-resistant Trichomonas vaginalis isolates calls for the search for new drugs to counter the pathogenicity of these parasites. Results: Classification models for predicting the antitrichomonas activity of molecules were built. These models were employed to screen antiprotozoal drugs, from which 20 were classified as active. The in vitro experiments showed moderate to high activity for 19 of the molecules at 10 μg/ml, while 3 compounds yielded higher activity than the reference at 1 μg/ml. The 11 most active chemicals were evaluated in vivo using Naval Medical Research Institute (NMRI) mice. Conclusion: Benznidazole showed similar results as metronidazole, and can thus be considered as a potential candidate in antitrichomonas therapy.Peer Reviewe