Allosteric Protein Modulation: What is it and Why is it Important?

February 7, 2012
1:00 pm - 2:30 pm EST


The advancing technology of high throughput screening is changing the type of molecules found; functional assays have supplanted sterically oriented binding assays and with that change has come an increasing incidence of detection of molecules that affect receptor function in ways different from binding. Since protein function is more physiologically more relevant, this, in turn, is changing the quality of the molecules that pharmacologists and medicinal chemists must deal with in the discovery and development process. These changes involve:

  • The way we screen for new drugs
  • The types of molecules we have to develop as therapeutic agents
  • The way we quantify drug activity for medicinal chemists in lead optimization

This course will deal with these issues and familiarize pharmacologists and chemists with the tools needed to exploit this potentially extremely fruitful area of new drug discovery. The course is designed to answer these questions:

  • What is protein allostery?
  • What makes allosteric molecules unique and how can this contribute to unique therapeutic properties?
  • How can we detect allosterism?
  • How can we quantify allosterism for chemical lead optimization?

This course is designed to equip pharmacologists and chemists to deal with this emerging area of pharmacology.

Lecture 1: Allosteric Protein Modulation: What is it and Why is it Important?

Course Description:

Functional proteins (receptors, enzymes, ion channels) sense their world and adjust their reactivity to it through the process of allostery. This extremely important thermodynamic mechanism is becoming increasingly prevalent in drug discovery as the highthroughput screens for new drugs have changed from simple orthosterically oriented assays such as binding to highly sophisticated and information-rich functional assays, i.e. more and more allosteric hits are being observed. In response to this influx, discovery scientists need to be aware of how to detect, describe and otherwise think about allosteric ligands. This first nodule discusses the history of allostery, the present model used to describe it (modulator / conduit / guest) and the unique properties of allosteric molecules.

Learning Objectives:

This session is designed to solve a problem, namely the use of thermodynamic principles and practical pharmacology to detect allostery as a mechanism of action in drug candidate molecules.

Students will learn why allosterism is a unique and therapeutically useful mechanism of action for drugs with special reference to the properties of allosteric molecules and what makes them different from conventional molecules that interact with the natural protein binding site. ; these data are directly relevant to making choices of chemical targets for new drug discovery programs.

Instructor Information: 
Terry KenakinTerry Kenakin Ph.D.
Professor, Department of Pharmacology
University of North Carolina School of Medicine
Chapel Hill NC

Instructor Biography:
Terrence Kenakin, Ph.D., is Professor in the Department of Pharmacology, University of North Carolina, Chapel Hill. Until August of 2011, Dr. Kenakin was director of research at GlaxoSmithKline Research and Development laboratories at Research Triangle Park, NC where he optimized drug activity assay systems for the discovery and testing of. allosteric molecules mostly for the treatment of diabetes. Before starting the major stint of his drug discovery career at GSK, Dr. Kenakin was an associate scientist at Burroughs-Wellcome in the U.K. which he joined after a post-doctoral fellowship at University College London, U.K. Dr. Kenakin earned his Ph.D. in Pharmacology at the University of Alberta, Edmonton Canada.

Dr. Kenakin is a member of many editorial boards as well as Co-editor-in-Chief of the Journal of Receptors and Signal Transduction. In addition, he has authored numerous articles and has written eight books on pharmacology, including the popular "A Pharmacology Primer".

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