Project Title: Mechanisms of action for novel drugs for treatment of neuromuscular diseases
Rozita Laghaei, PhD. PSC Research Scientist
The goal of this project is to study hypothesized drug binding sites on the voltage gated calcium channel (VGCC) that result in drug-modulated channel gating (stabilizing the open state of the channel). Specifically, a novel drug class (e.g. GV-58) was recently developed that acts as an agonist (holding channels open longer) and has therapeutic potential to treat diseases and other conditions that result in neuromuscular weakness. This drug targets the type of VGCCs that are expressed at synapses, but it is currently unknown where the drug binds to the channel or how it affects channel gating. We will study various novel analogs of GV-58 and hypothesize drug-channel interaction sites and proposed mechanisms for gating modulation using computational methods at different levels of complexity. In particular, we are interested in novel drugs that slow VGCC deactivation kinetics and therefore increase the flux of calcium through open channels. These channel gating modifiers are first-in-class therapeutics for the treatment of neuromuscular diseases. The focus of our studies would be the disease Lambert-Eaton myasthenic syndrome (LEMS) that causes neuromuscular weakness due to an auto-antibody attack and removal of a fraction of the presynaptic calcium channels at neuromuscular junctions. We propose to study the drug-binding sites, molecular mechanisms of interaction between different drugs and the channel, and the structural basis for the different bindings. This study will significantly advance our knowledge of the molecular mechanism of VGCC drug binding, providing new unerstanding that may lead to novel therapeutics for a variety of disorders that result in neuromuscular weakness.
Neuroscience, biology, chemistry and physics
Students will learn the basics of molecular dynamics simulations, They will learn to use NAMD and VMD, AutoDock Vina and Pymol softwares. In collaboration with Dr. Steve Meriney (Neuroscience Dept., University of Pittsburgh) and his lab members they will study the effects of different drugs on the voltage-gated Ca2+ channels. The students will learn how to use supercomputers. They will explore the mechanisms that might lead to novel LEMS treatment strategies.
Students will learn the molecular mechanisms of action for various novel analogs of GV-58 channel gating drugs that target presynaptic voltage-gated Ca2+ channels.
The student in this position will receive a stipend or an hourly wage.