Physical Sciences and Mathematics Commons^™

Ligand-Based Drug Design : I. Conformational Studies Of Gbr 12909 Analogs As Cocaine Antagonists; Ii. 3d-Qsar Studies Of Salvinorin A Analogs As Kappa Opioid Agonists, Deepangi Pandit

Dissertations

Ligand-based drug design (LBDD) techniques are applied when the structure of the receptor is unknown but when a series of compounds or ligands have been identified that show the biological activity of the interest. Generally, availability of a series of compounds with high activity, with no activity, and also with a range of intermediate activities for the desired biological target is required. It is common that structures of membrane-bound proteins (for example, monoamine transporter proteins and opioid receptor proteins) are unknown as these proteins are notoriously difficult to crystallize.

In Part I of this study, analogs of the flexible dopamine …

Ligand-Based Design Of Dopamine Reuptake Inhibitors : Fuzzy Relational Clustering And 2-D And 3-D Qsar Modleing, Milind Misra

Dissertations

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 …

Modeling Of Flexible Drug-Like Molecules : Qsar Of Gbr 12909 Analog Dat/Sert Selectivity, Kathleen Mary Gilbert

Dissertations

The dopamine reuptake inhibitor GBR 12909 and related dialkyl piperazine and piperidine analogs have been studied as agonist substitution therapies acting on the dopamine transporter (DAT) to treat cocaine addiction. Undesirable binding to the serotonin transporter (SERT) can vary greatly depending on the specific substituents on the molecule. This study uses Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices (CoMSIA) techniques to determine a stable and predictive model for DAT/SERT selectivity for a set of flexible GBR 12909 analogs.

Families of analogs were constructed from six pairs of naphthyl-substituted piperazine and piperidine templates identified by hierarchical clustering as …