The Current issue of “The view from here” is concerned with Allosterism in Drug Discovery.

The topic of this month’s newsletter from Drug Discovery Today is “Allosterism in Drug Discovery”.

It is some time (nearly 60 years) since the term “allostery” was coined and the subsequent seminal work of Jacob, Monod and Changeux dealing with allostery (for a personal perspective see here). It was a coincidence then that only a few days ago, I saw a notification that Professor Changeux has been awarded the 2018 Albert Einstein World Award of Science. So it was highly appropriate that this month’s Editors Choice deals with the topic of Allosterism in Drug Discovery. Allostery represents a wonderful tool in the armoury of the medicinal chemist to drug difficult targets or, alternatively to expand into different areas of chemical space or avoid unwanted effects of more traditional approaches to drugging targets.

The first article in this month’s offering is entitled: “Discovery of hidden allosteric sites as novel targets for allosteric drug design”, by Shaoyong Lu, Mingfei Ji, Duan Ni and Jian Zhang of Shanghai, China. In this article, the authors highlight that, in its unbound inactive state, allosteric sites are not visible in crystal structures. When a ligand binds, however, the ligand stabilizes a particular conformation of the protein, previously encrypted allosteric sites may be exposed. Identifying such sites is a challenging task and this article expands upon the computational and other techniques that have been used to identify such sites in proteins.


The second article in the series is a more theoretical approach to the concept of allostery in drug discovery. It is by Bin Zhou and Jesús Giraldo of the Universitat Autònoma de Barcelona, Spain. It is entitled: “Quantifying the allosteric interactions within a G-protein-coupled receptor heterodimer”. In this article, the authors outline a mathematical model capable of quantifying the allosteric interactions that can be found in a receptor heterodimer.


The final article in this month’s offering is: “Designed covalent allosteric modulators: an emerging paradigm in drug discovery” from Shaoyong Lu and Jian Zhang from the Shanghai Jiao Tong University, School of Medicine, Shanghai, China. The article outlines how covalent allosteric modulators share the benefits of enhanced half-life of action, potency and reduced potential for drug resistance found for standard covalent ligands. They have the added benefit over standard active site covalent ligands in that they have higher selectivity and a reduced potential for toxicity. The authors review recent progress in the design of such molecules and illustrate the review with real-world examples of successful compounds. The review discusses the breadth of protein targets that may be appropriate for this approach and outline potential challenges and future directions of this promising approach to drug discovery.


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 50 articles in peer-reviewed journals, written several book chapters and has held a number of patents. 

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