3D-QSAR studies on 4-Hydroxyphenylpyruvate Dioxygenase inhibitors by comparative molecular field analysis (CoMFA)

A comparative molecular field analysis (CoMFA) of alkanoic acid 3-oxo-cyclohex-1-enyl ester and 2-acylcyclohexane-1,3-dione derivatives of 4-hydroxyphenylpyruvate dioxygenase inhibitors has been performed to determine the factors required for the activity of these compounds. The substrate's conformation abstracted from dynamic modeling of the enzyme-substrate complex was used to build the initial structures of the inhibitors. Satisfactory results were obtained after an all-space searching procedure, performing a leave-one out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.779 and 0.989, respectively. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new HPPD ligands with predetermined affinities.

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered.

CoMFA and homology-based models of the glycine binding site of N-methyl-D-aspartate receptor

Homology modeling was used to build 3D models of the N-methyl-D-aspartate (NMDA) receptor glycine binding site on the basis of an X-ray structure of the water-soluble AMPA-sensitive receptor. The docking of agonists and antagonists to these models was used to reveal binding modes of ligands and to explain known structure-activity relationships. Two types of quantitative models, 3D-QSAR/CoMFA and a regression model based on docking energies, were built for antagonists (derivatives of 4-hydroxy-2-quinolone, quinoxaline-2,3-dione, and related compounds). The CoMFA steric and electrostatic maps were superimposed on the homology-based model, and a close correspondence was marked. The derived computational models have permitted the evaluation of the structural features crucial for high glycine binding site affinity and are important for the design of new ligands.

3D Curvature Contrast - a geometric or brightness illusion?

Simultaneous contrast effects have been found across a wide range of visual dimensions. We describe a simultaneous contrast effect - three-dimensional curvature contrast - in which the apparent curvature of a surface defined by shading and texture information is influenced by the curvature of a surrounding surface. The effect is strong and easily measurable. We asked whether the effect depends upon the presence of contrast at the level of the internal representation of surface curvature or whether it could be better explained in terms of local changes in the apparent brightness of regions within the test patches induced by luminance transition at the borders. The experimental results suggest that, whicle these luminance-contrast-induced effects do contribute to the observed changes in perceived curvature, there are additional influences. In particular changes in perceived curvature induced by a pattern of curved patches were eliminated or considerably weakened when the inducing pattern was transformed into a photographic negative, a procedure which disrupts the apparent three-dimensional structure of the surface patches without changing their brightness contrast. This suggests a component of the illusion involves comparisons at the level of representation of surface curvature. The observation that three-dimensional curvature contrast presists when the inducing surfaces are spatially separate from the test surface suggests that shape perception involves global, as well as local, operations.