In this issue, we will be discussing some of the most recent developments in Medicinal Chemistry as published in the pages of Drug Discovery Today. We cover a very wide range of topics, notably the development of a third year undergraduate project, which outlines the principles of drug development along with worked examples of how you would go about optimizing compound potency. The other articles deal with other aspects of medicinal chemistry in drug development, notably how you may be able to expand chemical space such that it impacts upon new and different targets. This is then complemented by an article outlining how conformational information can be blended into drug discovery programmes. Medicinal chemistry has been and continues to be one of the most popular and downloaded topics in the journal in spite of the increase in popularity and emphasis upon biological therapies. This is a testament both to the value of small molecular weight drug development and to the ingenuity of the practitioners of the discipline

The free downloads available in this newsletter highlight some of the most recent developments in Medicinal Chemistry. I will elaborate on them below.

The first article, by M. Jonathan Fray, Simon J.F. Macdonald, Ian R. Baldwin, Nick Barton, Jack Brown, Ian B. Campbell, Ian Churcher, Diane M. Coe, Anthony W.J. Cooper, Andrew P. Craven, Gail Fisher, Graham G.A. Inglis, Henry A. Kelly, John Liddle, Aoife C. Maxwell, Vipulkumar K. Patel, Stephen Swanson and Natalie Wellaway of the School of Chemistry, University of Nottingham, UK and GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK  entitled “A practical drug discovery project at the undergraduate level”  marks a departure from the normal article type published in Drug Discovery Today in that it deals with the development of a project aimed at Chemistry undergraduates with real world examples of  how ligands may be developed and improved through SAR. The project, a close collaboration between academia and industry, highlights how weak antagonists directed against phosphatidylinositide 3-kinase delta (PI3Kδ) may be optimized with respect to potency by examination of screening data and subsequent compound design. It is hoped that such approaches will be useful in attracting and training the next generation of medicinal chemists. 

The second article, by Andy Barker, Jason G. Kettle, Thorsten Nowak and J. Elizabeth Pease of AstraZeneca R&D, Oncology iMed, Alderley Park, Macclesfield, UK entitled: “Expanding medicinal chemistry space” outlines how currently-available clinically-useful drugs occupy a relatively well-defined chemical space. It is clear, however, that new, interesting and, as yet, inaccessible targets occupy chemical space that it not well utilized by current agents. This article highlights current strategies to address this issue and how expanding current chemical space may allow lead development in new targets and target classes. Such new approaches are reviewed and the authors highlight the potential for these strategies to generate new leads in drug development programmes.

Finally, is the review from Harry Finch, entitled: “The conformational musings of a medicinal chemist”.  This paper is involved with discussion of how, over the past 25 years, conformational data obtained from X-ray crystallography experiments and, more recently from computational studies, has been used to characterize and optimize the binding of ligands to their cognate sites in receptors. These data have become more and more reliable and have, therefore, developed  ever-increasing importance in defining the structure of useful medicinal compounds. The author goes on from here to discuss how new NMR techniques can be used to provide a full description of the conformation of ligands in solution. He proposes that the integration of such physically diverse data sources will provide a major impact on drug discovery in the future.

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. He has authored over 40 peer-reviewed articles, written several book chapters and has held a number of patents.