The Affinity Advantage
J. Med. Chem. 2026, 69, 3, 1963–1969
To start with, any Med Chem paper written by Mark Murcko is probably worth a read because as one of the key contributors to American medicinal chemistry over the last four decades, it’s worth listening to his experience. In this paper Mark argues¹ for continuously addressing optimizing affinity and then addresses seven benefits of doing so. Some of these are non -controversial: increasing cellular potency, optimizing close off target selectivity, avoiding the ‘avoid-ome’ – ie secondary pharmacology that might prove toxic, making more diverse compounds to act as an insurance against losing a series for some unexpected reason, whereas others: are less well argued. I’m unconvinced that emboldening teams to pursue synthetically challenging targets is a good thing in itself. If there’s compelling evidence to resource a hard to make compound, that makes sense, but if there are two compounds of equal predicted potency, but different levels of synthetic challenge, unless there was some other ADMET advantage, surely one would always choose the easier to make compound first?
The paper contains a thorough rebuttal of objections to continuing to address affinity. This section is a tour of the challenges of medicinal chemistry and also having to deal with the rhetoric of “whataboutary” instead of dealing with the uncomfortable question: “why can’t medicinal chemists design more potent compounds more quickly” – the excuses we come up with to avoid that issue. As a list of further reading the citations themselves makes an excellent reference resource.
To conclude: the strategy of persisting in pursuing compounds of high affinity is, though not at the expense of ADME properties, absolutely valid, the challenge for most of us is how to do it efficiently? Accurately predicting potency, despite advances in computational methods whether machine learning or physics based, remains a stubbornly difficult problem. Often, even with significant resources, finding ligand efficient compounds with sub 10nM potency takes us far too long and requires very significant chemical resourcing. We can only hope that current work in delivering better models and larger open source data sets can provide the foundational data that can be used to tackle this problem.²
(1) Murcko, M. A. The Affinity Advantage. J. Med. Chem. 2026, 69 (3), 1963–1969. https://doi.org/10.1021/acs.jmedchem.5c03222.
(2) Home | openbind.uk. https://openbind.uk/ (accessed 2026-03-31).