Ligand-based design of dopamine reuptake inhibitors : fuzzy relational clustering and 2-D and 3-D QSAR modleing

As the three-dimensional structure of the dopamine transporter (DAT) remains undiscovered, any attempt to model the binding of drug-like ligands to this protein must necessarily include strategies that use ligand information. For flexible ligands that bind to the DAT, the identification of the binding conformation becomes an important but challenging task. In the first part of this work, the selection of a few representative structures as putative binding conformations from a large collection of conformations of a flexible GBR 12909 analogue was demonstrated by cluster analysis. Novel structurebased features that can be easily generalized to other molecules were developed and used for clustering. Since the feature space may or may not be Euclidean, a recently-developed fuzzy relational clustering algorithm capable of handling such data was used. Both superposition-dependent and superposition-independent features were used along with region-specific clustering that focused on separate pharmacophore elements in the molecule. Separate sets of representative structures were identified for the superpositiondependent and superposition-independent analyses. In the second part of this work, several QSAR models were developed for a series of analogues of methylphenidate (MP), another potent dopamine reuptake inhibitor. In a novel method, the Electrotopological-state (B-state) indices for atoms of the scaffold common to all 80 compounds were used to develop an effective test set spanning both the structure space as well as the activity space. The utility of B-state indices in modeling a series of analogues with a common scaffold was demonstrated. Several models were developed using various combinations of 2-D and 3-D descriptors in the Molconn-Z and MOE descriptor sets. The models derived from CoMFA descriptors were found to be the most predictive and explanatory. Progressive scrambling of all models indicated several stable models. The best models were used to predict the activity of the test set analogues and were found to produce reasonable residuals. Substitutions in the phenyl ring of MP, especially at the 3- and 4-positions, were found to be the most important for DATbinding. It was predicted that for better DAT-binding the substituents at these positions should be relatively bulky, electron-rich atoms or groups

Robust techniques and applications in fuzzy clustering

This dissertation addresses issues central to frizzy classification. The issue of sensitivity to noise and outliers of least squares minimization based clustering techniques, such as Fuzzy c-Means (FCM) and its variants is addressed. In this work, two novel and robust clustering schemes are presented and analyzed in detail. They approach the problem of robustness from different perspectives. The first scheme scales down the FCM memberships of data points based on the distance of the points from the cluster centers. Scaling done on outliers reduces their membership in true clusters. This scheme, known as the Mega-clustering, defines a conceptual mega-cluster which is a collective cluster of all data points but views outliers and good points differently (as opposed to the concept of Dave\u27s Noise cluster). The scheme is presented and validated with experiments and similarities with Noise Clustering (NC) are also presented. The other scheme is based on the feasible solution algorithm that implements the Least Trimmed Squares (LTS) estimator. The LTS estimator is known to be resistant to noise and has a high breakdown point. The feasible solution approach also guarantees convergence of the solution set to a global optima. Experiments show the practicability of the proposed schemes in terms of computational requirements and in the attractiveness of their simplistic frameworks. The issue of validation of clustering results has often received less attention than clustering itself. Fuzzy and non-fuzzy cluster validation schemes are reviewed and a novel methodology for cluster validity using a test for random position hypothesis is developed. The random position hypothesis is tested against an alternative clustered hypothesis on every cluster produced by the partitioning algorithm. The Hopkins statistic is used as a basis to accept or reject the random position hypothesis, which is also the null hypothesis in this case. The Hopkins statistic is known to be a fair estimator of randomness in a data set. The concept is borrowed from the clustering tendency domain and its applicability to validating clusters is shown here. A unique feature selection procedure for use with large molecular conformational datasets with high dimensionality is also developed. The intelligent feature extraction scheme not only helps in reducing dimensionality of the feature space but also helps in eliminating contentious issues such as the ones associated with labeling of symmetric atoms in the molecule. The feature vector is converted to a proximity matrix, and is used as an input to the relational fuzzy clustering (FRC) algorithm with very promising results. Results are also validated using several cluster validity measures from literature. Another application of fuzzy clustering considered here is image segmentation. Image analysis on extremely noisy images is carried out as a precursor to the development of an automated real time condition state monitoring system for underground pipelines. A two-stage FCM with intelligent feature selection is implemented as the segmentation procedure and results on a test image are presented. A conceptual framework for automated condition state assessment is also developed

Neurological and Mental Disorders

Mental disorders can result from disruption of neuronal circuitry, damage to the neuronal and non-neuronal cells, altered circuitry in the different regions of the brain and any changes in the permeability of the blood brain barrier. Early identification of these impairments through investigative means could help to improve the outcome for many brain and behaviour disease states.The chapters in this book describe how these abnormalities can lead to neurological and mental diseases such as ADHD (Attention Deficit Hyperactivity Disorder), anxiety disorders, Alzheimer’s disease and personality and eating disorders. Psycho-social traumas, especially during childhood, increase the incidence of amnesia and transient global amnesia, leading to the temporary inability to create new memories.Early detection of these disorders could benefit many complex diseases such as schizophrenia and depression

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 377)

This bibliography lists 223 reports, articles, and other documents recently introduced into the NASA Scientific and Technical Information System. Subject coverage includes: aerospace medicine and physiology, life support systems and man/system technology, protective clothing, exobiology and extraterrestrial life, planetary biology, and flight crew behavior and performance

Pharmacological Characterization of Novel Opioid Receptor Ligands Aimed at Reducing the Development of Tolerance

The three opioid receptor subtypes, mu (mu), delta (delta) and kappa (kappa) have long been associated with analgesia. Traditional opioid analgesics exert their effects through mu receptors located in the CNS. Recent studies suggest that the development of opioid analgesics displaying dual properties of mu agonism and delta antagonism could be of benefit by retaining potent analgesic properties while reducing the development of tolerance with chronic administration. UMB 425 displays high affinity at the mu receptor (K i = 3.2 +/- 0.14 nM), moderate affinity at the delta and kappa receptor. In vitro [35S]GTPgammaS functional assay results indicate that UMB 425 acts as partial agonist at the mu receptor, whilst having competitive antagonistic properties at the delta receptor. UMB 425 displays potent acute analgesic activity in vivo for both the hot plate and tail-flick assays, comparable to morphine itself. Naloxone, a non-selective opioid antagonist, and nor-BNI, a selective kappa-antagonist, pretreatment studies were performed to ensure proper opioid-induced analgesic mechanisms. Naloxone attenuates the analgesic effects induced by an acute ED90 of UMB 425, while nor-BNI shows no significant reduction. A chronic dosing paradigm was designed to determine UMB 425 induced analgesic tolerance. UMB 425 maintains significantly higher levels of analgesia compared to morphine on the fifth day of this chronic dosing paradigm. A dose-response challenge performed on the sixth day of this paradigm indicates a smaller shift in respective ED50 values for UMB 425 as compared to morphine for both the tail-flick (1.3-/6.4-fold) and hot plate (3.0-/7.8-fold) assays, effectively demonstrating reduced analgesic tolerance liabilities for UMB 425

The use of Somatic Experiencing™ in the treatment of an adolescent with trauma-based obsessive-compulsive disorder

Abstract: When trauma precedes or coincides with the development of obsessive-compulsive disorder (OCD), a unique type of OCD develops. This is because, as the research shows, the neurophysiological reactions of trauma become “trapped” in the physiology of the client’s nervous system. Therefore, it is proposed that trauma adds an additional dimension to the treatment of OCD in paediatric and adolescent clients. It then becomes necessary to utilize a trauma-based treatment method, such as Somatic Experiencing™, to assist in resolving the obsessions and compulsions. The developmental features of adolescence are of particular interest to the area of educational psychology. It has been established through research cited in this thesis that childhood trauma significantly affects neuronal development and Autonomic Nervous System regulation, and creates a greater predisposition to mental illness in adolescence and adulthood.. The adolescent brain is well known for the increased expression of dopamine in the prelimbic Prefrontal Cortex which is instrumental in increasing motivational salience. Due to this factor, associations formed by the adolescent between a behaviour and the environment are more difficult to change compared with other maturational stages. (Baker, Bisby & Richardson, 2016)...Ph.D. (Educational Psychology