Pharmacological Analysis of pLGICs

The rich pharmacological regulation of pLGICs is a promising strategy to develop new therapies for a variety of diseases. Creative Bioarray is committed to using the detailed structural information of pLGICs family members to provide clients with professional pharmacological analysis services. We help clients analyze the pharmacology of structurally diverse drugs at topographically different sites to accelerate the design of future drugs targeting pLGICs.

Introduction

pLGICs are involved in the rapid chemical transmission of nerve signals in the central and peripheral nervous systems. Dysfunction of these channels is associated with several central nervous system diseases, including myasthenia gravis, hyperplexia, epilepsy, nicotine and alcohol addiction, schizophrenia, and Alzheimer's and Parkinson's diseases. Therefore, pLGICs have been used by the pharmaceutical industry as targets for the development of novel therapeutics against neurological diseases.

Pharmacological studies have shown that PLGICs are targets of structurally diverse allosteric modulators that bind to different sites. Notably, these receptors are targets of several classes of worldwide prescribed drugs, such as general anesthetics, anxiolytics, and anticonvulsants. These drugs allosterically modulate pLGIC function by acting on several distinct topological sites. Because these receptors undergo discrete allosteric transitions between multiple states and different pharmacological compounds select and stabilize structurally distinct conformations, it is necessary to understand the structures of all their allosteric states to elucidate the modulation mechanisms of existing drugs.

Fig. 1 Transmembrane pharmacology in pLGIC. (Sauguet, 2005)

Our Services

We focus on the extended field of pGLIC structural molecular biology to promote the mechanism rationalization of existing drugs and identify new drug binding sites. Our services include but not limited to:

• Crystallographic analysis of pGLICs binding sites.
  We help our clients obtain the structures of ligand-bound pGLICs to provide insights into the binding sites of several important agonists, allosteric modulators and inhibitors. The fact that the ligand-binding structures of pGLICs are solved at a resolution between 2.7 and 3.9 Å makes it difficult to assign small ligands to the electron density. We realize the specific localization of these atoms in the electron density by using the anomalous scattering of some atoms at or near their X-ray absorption edges.
• Analysis of allosteric transitions in pLGICs.
• Analysis of the neurotransmitter orthosteric binding site.
• Allosteric site analysis in the extracellular domain (ECD).
  Agonist responses are regulated by structurally diverse molecules that target topographically different sites in ECD. We help our clients analyze how the ELIC structural model allows the identification of several binding sites for benzodiazepines and divalent cations to allosterically regulate agonist responses.
• Allosteric site analysis in the transmembrane domain (TMD).
  TMD is the target of many allosteric modifiers, such as ethanol and other alcohols, general anesthetics (GA), and lipids. We help customers analyze modulation sites for alcohols and GA, including intrasubunit GA modulatory site, intersubunit GA modulatory site and Ion channel GA binding site, as well as intrasubunit phospholipid-binding site in the TMD.
• Binding affinity prediction by computational methods.

Creative Bioarray has the strength to provide customers with high-quality pharmacological analysis services of pGLICs, providing useful information for understanding the mechanism of allosteric modulators that selectively favor one conformation of the receptor rather than another. If you are interested in our services, please contact us for more details.

Reference

1. Sauguet, L.; et al. Crystallographic studies of pharmacological sites in pentameric ligand-gated ion channels. Biochimica et Biophysica Acta (BBA)-General Subjects, 2015, 1850(3): 511-523.