Impact assessment of the rational selection of training and test sets on the predictive ability of QSAR models.

This study performed an analysis of the influence of the training and test set rational selection on the quality and predictively of the quantitative structure-activity relationship (QSAR) model. The study was carried out on three different datasets of Influenza Neuraminidase (H1N1) inhibitors. The three datasets were divided into training and test sets using three rational selection methods: based on k-means, Kennard-Stone algorithm and Activity and the results were compared with Random selection. Then, a total of 31,490 mathematical models were developed and those models that presented a determination coefficient higher than: r2train > 0.8, r2loo > 0.7, r2test > 0.5 and minimum standard deviation (SD) and minimum root-mean square error (RMS) were selected. The selected models were validated using the internal leave-one-out method and the predictive capacity was evaluated by the external test set. The results indicate that random selection could lead to erroneous results. In return, a rational selection allows for obtaining more reliable conclusions. The QSAR models with major predictive power were found using the k-means algorithm and selection by activity.

Structure-activity relationship on excitatory amino acid receptors.

It is generally accepted that the carboxylic amino acids L-Glu and L-Asp play a role as excitatory neurotransmitters at the CNS. In the search of a structure-activity relationship we have made a theoretical conformational analysis with a mechanics molecular model on active compounds on QUIS and NMDA-receptors. We consider the COO-...COO- distance in these compounds as the more important one in order to discuss the different mode of action of this compound at the excitatory amino acid receptors. On QUIS-receptors: We had found that Glu, Asp and QUIS are very flexible molecules that can easily pass from one conformation to another and to get the distance of 3A degrees between the two COO- groups. All these compounds show an important population in conformations with this distance. The antagonist GDEE had 90% of its whole population in folded conformations with a distance of about 3 A degrees between COO-...COO- groups. On NMDA-receptors: IBO is a rigid analogue and the distance COO-...COO- is about 4A degrees at the different conformations found. Asp, Glu, beta-Amglu and NMDA have a considerable flexibility and they can easily adopt the distance required. They leave a considerable population in conformations that present a COO-...COO- distance about 4A degrees. We propose that folded conformations are important for activity on QUIS-receptors, whereas extended conformations are the important on NMDA-receptors.

Structure-activity relationship on excitatory amino acid receptors

Actualmente se acepta que los aminoácidos carboxílicos L-Glu y L-Asp tienen un rol como neurotransmisores excitatorios en el sistema nervioso contral (CNS). En el presente trabajo hemos realizado un análisis teórico conformacional con un modelo de mecánica molecular sobre compuestos activos en QUIS y NMDA-receptores, en la búsqueda de una correlación estructrura-actividad. En estos compuestos, consideramos la distancia COO-..COO- como la más importante para el análisis de la actividad de los mismos sobre los distintos receptores de aminoácidos excitatorios. Sobre los QUIS-receptores: Hemos encontrado que Glu, Asp son móleculas muy flexibles que pueden pasar con facilidad de una conformación a otra y alcanzar la distancia de 3A- entre los dos grupos COO-. Todos estos compuestos muestran una importante población en conformaciones con esta distancia. El antagonista GDEE tiene un 90% de la población total en conformaciones plegadas con una distancia de alrededor de 3A- entre los grupos COO-. Sobre los NMDA-receptores: IBO es un análogo rígido y la distancia COO-..CO- es alrededor de 4A- en las diferentes conformaciones encontradas. Asp. Glu, ß-Amglu y NMDA tienen una considerable flexibilidad y pueden adoptar fácilmente las distancia requeridas. Ellos poseen una considerable población en conformaciones que presentan una distancia COO-..COO- de alrededor de 4A-. Se propone que conformaciones plegadas son importantes para la actividad en QUIS-receptors, mientras conformaciones extendidas serían importantes en NMDA-receptors

Struture activity relationship in GABA receptors / Relación estructura actividad en receptores de GABA

Isoguvacine, isonipecotic acid, THIP and muscimol, agonist on GABA-receptors, were studied, looking for a structure-activity relationship. In this way, a conformational analysis was performed with an empirical atom-atom potential calculation method that was proved with success in previous works on biologically active substances. It has been assumed that hydration should eliminate electrostatic interactions and consequently, calculations are performed on molecules without charges. Muscimol, THIP, isoguvacine and isonipecotic acid are rigid structural analogues of GABA. The conformational analysis yield following result. Muscimol show a free rotation but, for different positions of the rotational group. a distance of 4,4 A- between CO and N was obtained. For the other compounds studied, twisted conformation was obtained, with an important population in each case. For these conformations a common pattem to all of them was found: adistance of about 4,4 A- betweeb the CO and N groups. This distance is found in partially folded (gauche-trans) conformations of GABA, with a 50% of the whole population. Then, we assumed that partially folded conformations, with a distance between potentially active sites of 4,4 A- may be important for the recognition at the BABA-receptors

Estudio conformacional, utilizando un potencial atomo-atomo empirico, de aminoacidos biologicamente activos como neurotransmisores. / Conformational study,using an empirical atom-atom potential of biologically active amino acids as neurotransmitters

En la busqueda de una correlacion conformacional que justifique su actividad, se ha estudiado un conjunto de aminoacidos biologicamente activos, y a los cuales se asigna un papel como neurotransmisores: Glutamico, GABA, Aspartico, beta-alanina y taurina. Se estudiaron los zwitter-ion de estos aminoacidos, por ser la especie preponderante a pH fisiologico, empleando como metodo de calculo un potencial atomo-atomo empirico. Como en estudios anteriores, se suposo que la hidratacion eliminaria las interacciones electrostaticas y, consecuentemente, los calculos se realizaron como si las especies no tuvieran cargas. Los resultados obtenidos en las conformaciones de minima energia, en las distancias interatomicas entre grupos presumiblemente activos y en las poblaciones conformacionales, estan en excelente acuerdo con los resultados experimentales de RMN en solucion acuosa