Cytotoxic oplopane sesquiterpenoids from Arnoglossum atriplicifolium.

Pale Indian plantain (Arnoglossum atriplicifolium (L.) H. Rob.

Inhibition of the thioesterase activity of human fatty acid synthase by 1,4- and 9,10-diones.

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo.

Orbital energetics and molecular recognition.

We present preliminary data demonstrating that orbital eigenenergy fluctuation recorded in the course of ab initio molecular dynamics calculations may contain information relevant in determining molecular behavior and recognition. A simple scheme is presented that maps these data to molecular descriptors. Using computational drug design as the context, these descriptors are compared with previous electronic eigenvalue descriptor methods with encouraging results.

QSAR modeling of mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating dopamine release.

Back-propagation artificial neural networks (ANNs) were trained on a dataset of 42 molecules with quantitative IC50 values to model structure-activity relationships of mono- and bis-quaternary ammonium salts as antagonists at neuronal nicotinic acetylcholine receptors (nAChR) mediating nicotine-evoked dopamine release. The ANN QSAR models produced a reasonable level of correlation between experimental and calculated log(1/IC50) (r2=0.76, r(cv)2=0.

Supervised self-organizing maps in drug discovery. 2. Improvements in descriptor selection and model validation.

The modeling of nonlinear descriptor-target relationships is a topic of considerable interest in drug discovery. We, herein, continue reporting the use of the self-organizing map-a nonlinear, topology-preserving pattern recognition technique that exhibits considerable promise in modeling and decoding these relationships. Since simulated annealing is an efficient tool for solving optimization problems, we combined the supervised self-organizing map with simulated annealing to build high-quality, highly predictive quantitative structure-activity/property relationship models.

Molecular modeling of mono- and bis-quaternary ammonium salts as ligands at the alpha4beta2 nicotinic acetylcholine receptor subtype using nonlinear techniques.

The neuronal nicotinic acetylcholine receptor (nAChR) has been a target for drug development studies for over a decade. A series of mono- and bis-quaternary ammonium salts, known to be antagonists at nAChRs, were separated into 3 structural classes and evaluated using both self-organizing map (SOM) and genetic functional approximation (GFA) algorithm models. Descriptors from these compounds were used to create several nonlinear quantitative structure-activity relationships (QSARs).

Supervised self-organizing maps in drug discovery. 1. Robust behavior with overdetermined data sets.

The utility of the supervised Kohonen self-organizing map was assessed and compared to several statistical methods used in QSAR analysis. The self-organizing map (SOM) describes a family of nonlinear, topology preserving mapping methods with attributes of both vector quantization and clustering that provides visualization options unavailable with other nonlinear methods. In contrast to most chemometric methods, the supervised SOM (sSOM) is shown to be relatively insensitive to noise and feature redundancy.

Protonation-induced stereoisomerism in nicotine: conformational studies using classical (AMBER) and ab initio (Car-Parrinello) molecular dynamics.

A variety of biologically active small molecules contain prochiral tertiary amines, which become chiral centers upon protonation. S-nicotine, the prototypical nicotinic acetylcholine receptor agonist, produces two diastereomers on protonation. Results, using both classical (AMBER) and ab initio (Car-Parrinello) molecular dynamical studies, illustrate the significant differences in conformational space explored by each diastereomer.

2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands.

A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g.

Genetic algorithms and self-organizing maps: a powerful combination for modeling complex QSAR and QSPR problems.

Modeling non-linear descriptor-target activity/property relationships with many dependent descriptors has been a long-standing challenge in the design of biologically active molecules. In an effort to address this problem, we couple the supervised self-organizing map with the genetic algorithm. Although self-organizing maps are non-linear and topology-preserving techniques that hold great potential for modeling and decoding relationships, the large number of descriptors in typical quantitative structure-activity relationship or quantitative structure-property relationship analysis may lead to spurious correlation(s) and/or difficulty in the interpretation of resulting models.

Targacept active conformation search: a new method for predicting the conformation of a ligand bound to its protein target.

Targacept active conformation search (TACS) is a novel variation of well-established three-dimensional quantitative structure--activity relationship methodologies that seeks to determine probable conformation(s) of ligands bound to their protein targets. A combination of affinity or activity data and energetically accessible conformational ensembles, each conformer described by three-dimensional (3-D) sensitive descriptors, forms the basis of the TACS data model. Recursive pruning is used to reduce the size of both the conformational ensemble and the descriptor space until the TACS data model contains just enough information to determine probable conformation(s) of ligands bound to their protein targets.

Mapping potential energy surfaces.

A recently proposed dynamical method [A. Laio and M. Parrinello, Proc.

Targeting neuronal nicotinic receptors: a path to new therapies.

The structural heterogeneity, the ubiquity of anatomical distribution, and the demonstrated modulation of biological functions is consistent with the view that nicotinic cholinergic signaling plays a key regulatory role in the brain and influences a number of neuronal processes including sensory processing, motor activity, and cognitive function. It has become evident that perturbation of nicotinic cholinergic neurotransmission can result in diverse CNS pathologies providing the potential for therapeutic intervention in a number of neurodegenerative, neuropsychiatric and neurological disorders. This review will provide a status on the rationale for neuronal therapies targeting neuronal nicotinic receptors (nAChRs) and discusses the multifaceted beneficial effects than can be achieved through manipulation of cholinergic pharmacology.

Computation, visualization, and animation of infrared Mueller matrix elements by scattering from surfaces that are absorbing and randomly rough.

Computation of Mueller matrix elements by infrared scattering from randomly rough two-dimensional surfaces and results of a method for graphic display of the data are presented. A full wave electromagnetic scattering model first generates raw data elements of the 4 × 4 Mueller matrix F(θ, nλ, kλ, σs(2), ?h(2)?) in beam backscattering angle (θ) ranging from normal to oblique incidence, in refractive index of the beam scatterer (nλ - ikλ) spanning the 9 ≤ λ ≤ 12.5 µm midinfrared band, and in mean-squared slope ((σS(2)) and mean-squared height (?h(2)?) of the scattering surface.