This month’s Drug Discovery Today Editor’s Choice newsletter is concerned with the field of ADME-Tox. We are highlighting aspects of this rapidly-expanding discipline with some recently published reviews from the pages of Drug Discovery Today.
The first free download is hot off the press is from Friederike Stoll, Andreas H.Göller and Alexander Hillisch of Bayer Health Care, who address the topic of: “Utility of protein structures in overcoming ADMET-related issues of drug-like compounds”. This article reviews how the recent increase in availability of solved X-ray structures of proteins relevant to drug discovery and, hence, ADME-Tox, has allowed a complementary approach, blending elements of quantitative structure–property relationships with a more protein structure-based view. Such an approach complements and extends both approaches synergistically. In this review they discuss the utility of protein-structure-based design and docking approaches aimed at overcoming issues related to plasma protein binding, active transport via P-glycoprotein, hERG channel-mediated cardiotoxicity and cytochrome P450 inhibition, metabolism and induction.
Following on from this, the next paper in our offering is from Timothy J. Ritchie, Peter Ertl and Richard Lewis, who discuss issues related to the visualisation and utilization of the ADME properties of molecules in: “The graphical representation of ADME-related molecule properties for medicinal chemists”. Scientists do not, or should not, work in isolation; some of the benefit of the results arising from the ADME studies in early phase drug discovery are in the design of molecules with more favourable drug-like characteristics. To allow this to happen, it is essential to present the results of ADME experiments to the medicinal chemist in a format that they can easily understand and assimilate into their design.
Next in the selection is the article by Cédric Merlot on: “Computational toxicology—a tool for early safety evaluation”. In this paper, Merlot discusses how an appropriate blend of in vivo, in vitro and in silico methodologies can be used early in the drug discovery process to ameliorate safety issues. He discusses how introduction of these tools could help to improve the pharmacokinetic properties of drug candidates, which might also help in the reduction of attrition of molecules as a result of unfavourable PK properties.
Last, but by no means least, is the contribution from Sean Ekins, J. Dana Honeycutt and James T. Metz on: “Evolving molecules using multi-objective optimization: applying to ADME/Tox”. This review deals with how, nowadays, drug discovery and development involves the simultaneous optimization of biological (potency, selectivity etc.) and physicochemical properties of molecules. The particular focus of this article relates to the simultaneous improvement of ADME-Tox properties using Pareto optimization.
I hope that you enjoy these articles and that they might spur you to think about ADME-Tox in a different light. Should you have any comments or suggestions for future newsletters, I’d be glad to hear from you on s.carney@elsevier.com
Steve Carney was born in Liverpool, England studied Biochemistry at Liverpool University, obtaining a BSc.(Hons). He then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University. On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London 1, where he worked with Professor Helen Muir FRS on the biochemistry of experimental Osteoarthritis. Later, he joined Eli Lilly and Co. where he stayed for 15 years and held a number of positions in Biology R&D, initially in Connective Tissue, but latterly in Neuroscience. He left Lilly in 2002 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.