The first article in the Newsletter is Fragment-based drug discovery using cryo-EM, by Michael Saur, Michael J.Hartshorn, Jing Dong, Judith Reeks, Gabor Bunkoczi, Harren Jhoti and Pamela A. Williams of Astex Pharmaceuticals and Isohelio Ltd. Cryo EM is an incredibly important tool for the determination of high-resolution protein structure at levels that are useful for driving drug discovery. The technique is so significant that it was the subject of the Nobel Prize for Chemistry in 2017 for Jacques Dubochet, Joachim Frank and Richard Henderson. The technique has been one of the enabling technologies capable of incorporating structural biology into the drug discovery workflow. This article outlines how cryo-EM is now sufficiently powerful, reproducible and capable of throughput for it to make it compatible with fragment-based drug discovery. The authors illustrate this compatibility using test systems.

 

The second article in the newsletter concentrates upon the structure and molecular of an interesting and significant class of drug target. The authors, Lei Xu, Xiaoqin Ding, Tianhu Wang, Shanzhi Mou, Huiyong Sun and Tingjun Hou in their article “Voltage-Gated Sodium Channels:Structures, Functions and Molecular Modeling” discuss the structure of this class of transmembrane channels involved in a wide range of pathologies, including epilepsy, cardiac arrhythmia and neuropathic pain. They outline developments in the understanding of the various structures and biological functions of members of this class and discuss in depth 8 pharmacologically-distinct ligand binding sites. They expand upon this though a commentary on molecular modeling and computer-aided drug design based around these channels.

 

The third and final article in this month’s offering is “Human ether-à-go-go-related potassium channel: exploring SAR to improve drug design” which departs from the other papers, in that the authors:  Maria Maddalena Cavalluzzi, Paola Imbrici, Roberta Gualdani, Angela Stefanachi, Giuseppe Felice Mangiatordi, Giovanni Lentini and Orazio Nicolotti deal with the SAR of a target that in the past had been seen as something to avoid, as a result of its tendency to produce cardiac toxicity (namely Torsade de Pointes). This pariah of drug targets is now, however, being seen in a more positive light as a result of its potential to address a number of pathologies in indications such as oncology, short QT syndromes, muscle atrophy and potentially cardiovascular indications. The article is a tour de force of the SAR of hERG channels and the possibility of minimizing cardiotoxicity and opening up new indications for such molecules.

 

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.