Traditional drug discovery was predicated upon the hypothesis that drug occupancy of receptors, particularly TM GPCRs, was responsible for eliciting a response within the cell. In the right situation, such a response could translate into a beneficial effect within the cell, reducing downstream effects or enhancing the effects of endogenous molecules. In any case, a direct binding to a cogent ligand binding site could modulate cell behaviour and hopefully have an effect on pathology. There is no doubt that such an hypothesis has been responsible for the development of many useful drugs, but more recently, it has become clear that a different approach can also be introduced into the drug discovery pipeline to develop compounds that may have an effect without interfering directly on the ligand binding site and subtly modulate the effects of receptors. This approach has been the allosteric modulation of receptors and has the advantage of being able to alter the potency of natural ligands by binding to a remote site of the protein. There are many potential advantages to this approach, not least that the unstimulated state of the receptor is effectively unchanged, but also it is possible that off-target effects may be minimized.
The free downloads available in this newsletter highlight some of the most recent developments in allosterism in drug discovery. I will elaborate on them below.
The first article, by Bruce J. Melancon, James C. Tarr, Joseph D. Panarese, Michael R. Wood and Craig W. Lindsley of the Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, entitled “Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer’s disease” discusses how various glutamatergic receptors can be involved in the development and adverse events associated with Alzheimer’s Disease. In particular the authors highlight the current interest in modulating muscarinic receptors to modify cholinergic transmission in the forebrain of Alzheimer’s sufferers. The M1 receptor is highly expressed in regions of the brain associated with memory, learning and cognition and therefore represents an attractive target for therapies to address these deficits in the Alzheimer brain. They outline the modest successes of the compound Xanomeline in the disease and highlight approaches in M1 allosteric modulation and how they may be useful in the future treatment of dementias.
The second article, from Shaoyong Lu, Wenkang Huang and Jian Zhang of the Department of Pathophysiology, Chinese Ministry of Education, Shanghai JiaoTong University, School of Medicine, Shanghai 200025, China entitled: “Recent computational advances in the identification of allosteric sites in proteins”, outlines the value of an allosteric approach to drug discovery and how computational methods can be used to identify allosteric sites in proteins. They review state-of-the-art computational approaches directed at predicting putative allosteric sites in proteins, along with examples of successes in identifying allosteric sites. They consider the challenges in developing reliable methods and tactics for predicting allosteric sites.
Finally, is the review from Lorenzo Palmieri and Giulio Rastelliof the Department of Life Sciences, University of Modena Italy, entitled: “αC helix displacement as a general approach for allosteric modulation of protein kinases”. Protein kinases represent a huge group of signaling molecules that effect a similarly large number of pathways. They have been shown to be involved in a wide range of diseases, notably cancer and inflammation inter alia. Historically, drugs to inhibit the action of such kinases generally were targeted against the ATP binding site. Although effective, there is such a high degree of homology between various ATP sites that the resultant drugs were frequently promiscuous, affecting many different protein kinases with resultant lack of selectivity. Although some drugs were produced that were highly selective, this was the exception rather than the norm and therefore, great interest in developing drugs directed at allosteric sites in these enzymes became of great interest as a tactic for developing potency and selectivity in this class of targets. Moreover, the allosteric modulators produced subtly different responses in the signaling pathway than had been possible with drugs merely interfering with ATP occupancy.
Steve Carney was born in Liverpool, England and studied Biochemistry at Liverpool University, obtaining a BSc.(Hons) and then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University, in the Departments of Medical Biochemistry and Histopathology. On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London, where he worked with Professor Helen Muir FRS and Professor Tim Hardingham, on the biochemistry of experimental Osteoarthritis. He joined Eli Lilly and Co. and held a number of positions in Biology R&D, initially in the Connective Tissue Department, but latterly in the Neuroscience Department. He left Lilly to take up his present position as Managing Editor, Drug Discovery Today, at Elsevier. Currently, he also holds an Honorary lectureship in Drug Discovery at the University of Surrey, UK. He has authored over 40 peer-reviewed articles, written several book chapters and has held a number of patents.