Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation.

Objective: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation.

Methods: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation.

A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy.

Objective: Many previous studies of drug repurposing have relied on literature review followed by evaluation of a limited number of candidate compounds. Here, we demonstrate the feasibility of a more comprehensive approach using high-throughput screening to identify inhibitors of a gain-of-function mutation in the SCN8A gene associated with severe pediatric epilepsy.

Methods: We developed cellular models expressing wild-type or an R1872Q mutation in the Na 1.

Synthesis and evaluation of the anti-proliferative and NF-κB activities of a library of simplified tylophorine analogs.

Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort.

Evaluation of Density Functionals, SCC-DFTB, Neglect of Diatomic Differential Overlap (NDDO) Models and Molecular Mechanics Methods for Prolyl-Leucyl-Glycinamide (PLG) and Structural Derivatives.

Prolyl-leucyl-glycinamide (PLG) is a unique endogenous peptide that modulates dopamine receptor subtypes of the D(2) receptor family within the CNS. We seek to elucidate the structural basis and molecular mechanism by which PLG and its analogues modulate dopamine receptors, toward the development of new therapeutics to treat Parkinson's disease, tardive dyskinesia and schizophrenia. As a first step toward establishing a validated protocol for accurate computational modeling of PLG and associated peptidomimetic analogues, we evaluated the accuracy of density functional theory (DFT), wavefunction theory (WFT), and molecular mechanics (MM) calculations for PLG and for a library of structurally related small molecules.