I hope that you’ll forgive me for including another Editor’s Choice newsletter with the topic of Medicinal Chemistry. I know that it is only fairly recently that I sent out a newsletter on training future Medicinal Chemists, emphasizing some of the joint ventures between Academia and Big Pharma. I feel justified in doing so, in that Medicinal Chemistry still comprises the bulk of the drug discovery efforts in many Pharma companies. I also feel that small molecule discovery is likely to continue to contribute significantly to future drug applications and approvals. Moreover, the topics involved in this mailing do not cover Medicinal Chemistry and synthesis per se, but rather techniques and approaches that may guide and aid the selection and development of small organic molecules to streamline the selection and decision process. So, a bit different from dyed-in-the-wool Medicinal Chemistry then. I hope you agree.

The first article of this month’s trilogy, is by Rutger H.A. Folmer, of the Department of Structure & Biophysics, Discovery Sciences, AstraZeneca R&D, Mölndal SE-431 83, Sweden   entitled: “Integrating biophysics with HTS-driven drug discovery projects”. I guess to the purists, this is not strictly a medicinal chemistry article, but I think it is of interest to the medicinal chemistry fraternity in that it outlines methodologies allowing the triage of hits from HTS campaigns, by the introduction of various biophysical tools. The article highlights the value of this approach in mode of action elucidation and validation of the screening cascade employed in HTS campaigns. Moreover, the author illustrates the value of the approach by outlining the top line results of 20 in-house projects from AstraZeneca. Nothing beats real-world data.

The second featured article, by Patrick Barton and Robert J. Riley of The School of life Sciences, University of Nottingham, Nottingham, UK and Evotec UK, Abingdon, Oxfordshire, UK is entitled: “A new paradigm for navigating compound property related drug attrition”. Again, this is an article outlining an approach to improve and streamline the drug selection process; improving efficiency and reducing late stage attrition. Obviously, this is of great significance in the “fail early, fail cheap” philosophy. The authors outline a hybrid chemical space, incorporating more well-known and understood chemical and ADMET drug properties with an increased emphasis on maximizing enthalpic properties and interactions key to drug transporter systems. The authors suggest that incorporation of the algorithms derived from this approach will provide a new index with the potential to bridge lipophilic efficiency and ADMET properties, potentially maximising target engagement yet reducing drug– transporter interation. This is beneficial since such interactions are thought frequently to produce drug:drug interations and potentially, toxicity.

Last, but by no means least, is the article from Renato A. Bauer, of Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, USA  entitled: “Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies “. He outlines how covalent inhibitors have had a long and illustrious history and are likely to continue to make major contributions in medicine. He also points out, however, that they have been viewed by many as molecules that have been viewed cautiously as having high potential for toxicity. Contrary to that view, such covalent inhibitors, as a result of less frequent dosing schedules, can prove to have very large therapeutic windows. Furthermore, the author points out that one of the potential benefits of covalent inhibitors is that they seem to have a much lower potential for the development of resistance, making them interesting candidates for conditions such as infectious disease and cancer.

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.