The practice of medicinal chemistry

Medicinal chemistry as a discipline has contributed enormously to gains in public health over the past century.

Medicinal chemistry as a discipline has contributed enormously to gains in public health over the past century. From aspirin to antibiotics, from modern psychiatric medicine to birth control and from cardiovascular treatments to therapies that mean cancer may not be the life sentence it once was; the impact is clear. Yet we stand at a crossroads. Just as the scientific basis for medicinal chemistry is distilled into guidelines and understanding, so advances in the molecular and genetic characterization of disease states means the range and nature of the targets we must actively engage with is increasing. As a mature discipline, what we have learned before will help us on this journey, but that alone will not be sufficient. Medicinal chemists must adapt, improve and challenge our concepts of what is druggable.

In this issue of Drug Discovery Today Editor’s Choice, I direct the interested reader to four recent reviews that highlight developments in the thinking of, and practice of certain aspects of medicinal chemistry which the authors believe are central to the further positive transformation of this important discipline.
In a thought-provoking review titled ‘Medicinal chemistry matters – a call for discipline in our discipline’, Craig Johnstone reflects on the increasingly scientific basis for the long empiric art of medicinal chemistry, enabled by analysis of broad data sets leading to industry accepted paradigms such as ‘Rule of 5’, Ligand Efficiency, LipE and ‘Leadlike’ property considerations. To this he contrasts recent analyses that indicate even now how strongly divergent drug design strategies exist between and even within individual organisations. In support of these arguments, two distinct optimisation pathways for a series of Akt inhibitors, from an identical start point are described, where synthetic tractability considerations deliver a significantly different (and inferior) optimisation outcome compared with a strategy based on control of molecular properties. The article concludes with practical suggestions on behaviours that might be employed in further incremental improvements in our discipline.
In contrast, with Andy Barker, Thorsten Nowak and Elizabeth Pease, in our article titled ‘Expanding medicinal chemistry space’, we try to articulate that while traditional hit generation and optimisation techniques continue to work well for established targets that have proved druggable in the past, a wide range of important and biologically attractive target classes remain largely intractable. Increasingly, demand is on medicinal chemists to move into unfamiliar chemical space and to challenge perceived notions of what is and is not drug-like. Medicinal chemistry in both industry and academia is responding to such challenges with the development of concepts such as diversity- and biology-oriented synthesis, and in the widespread application of fragment-assisted optimisation strategies. However success may only be realised through closer interdisciplinary collaboration and further advances in drug delivery and phenotypic and broader screening technologies.
The power of developments in synthetic chemistry methodology to drive access to new medicinal chemistry space is the highlight of an excellent review by Hong Shen and Thomas Graham titled ‘Gold-catalysed formation of heterocycles – an enabling new technology for medicinal chemistry’. Reactions are based upon the activation of alkynes and allenes that lead to efficient cycloisomerization products. The unique combination of the reactivity, safety and functional group tolerability of gold has been utilized to deliver an enormously diverse array of heterocycles relevant to drug discovery, with many examples containing dense functionality.
In an intriguing review titled ‘Subtleties in GPCR drug discovery: a medicinal chemistry perspective’, Masahiko Fujioka and Naoki Omori underscore the critical importance of the selection of suitable endpoints within a relevant assay format to ensure exploration of potentially hidden SAR. The tendency of GPCR ligands to induce different functional consequences based on small changes in structure is well known. Established medicinal chemistry optimization strategies such as changing the nature and position of substituents, modulating stereochemistry or restricting conformational freedom may routinely cause a switch between antagonism, and partial and inverse agonism. What is perhaps less appreciated by medicinal chemists is that our understanding of the true mechanism of target modulation may be influenced by receptor density and the nature of the agonist response itself.
This truly is an exciting time for those dedicated to the practice of medicinal chemistry. Despite enormous advances in our discipline in recent decades, unmet medical need remains high, and the challenges we face to deliver meaningful advances in public health are as significant now as they ever were.
Jason Kettle is Principal Scientist in medicinal chemistry in the oncology innovative medicines unit of AstraZeneca Pharmaceuticals at Alderley Park in the northwest of England.  He has extensive experience optimising drugs against a wide range of oncology, respiratory and inflammation targets, with particular expertise in the field of kinase inhibitor research and lead generation strategies.  He has published 29 articles in peer-reviewed journals and is named author on 37 patent applications.

Share this article

More services


This article is featured in:
The View From Here


Comment on this article

You must be registered and logged in to leave a comment about this article.