Publications and Presentations

When Two are not Enough: Lead optimisation beyond matched pairs

This article, co-authored with Noel O’Boyle and Roger Sayle of Optibrium NextMove Software, was published in Drug Discovery World.

It discusses how matched series analysis goes beyond matched molecular pairs to identify more relevant chemical substitutions with which to improve target potency.

matched molecular pairs article screenshot


Lead optimisation projects progress by making successive enhancements to one or more starting structures. This is a classic multi-objective optimisation procedure where the goal is not only to improve potency but also to improve physicochemical and absorption, distribution, metabolism and elimination (ADME) properties. Consequently, for physicochemical and ADME properties, the popular matched molecular pair analysis method has been a successful strategy. However, it notably fails in the goal of improving potency.

Here we discuss a lead optimisation approach involving matched series, the extension of matched pairs to more than two R-groups. This can successfully be used to guide molecular design towards improved potency. Furthermore, the approach retains the attractive features of matched pair analysis in that it is entirely driven by experimental data. It is also a natural fit to the medicinal chemistry approach of designing analogs by successive small changes to an existing molecule.



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