Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery. Hann, Leach and Harper

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J . Chem. Inf. Comput. Sci. 2001, 41, 856-864

At the heart of this paper is a delightfully simple thought experiment with obvious relevance to medicinal chemistry. There is a tension involved in testing molecules: the more molecular recognition features they contain, the more ways there are for them NOT to make a good set of interactions with a binding site. However, it is only when a molecule contains enough molecular recognition features that it can make an interaction that is strong enough to a) be detected and b) be useful. These two trends are in opposition to one another and lead to a maximum likelihood of observing a “useful” interaction that is summarised by the orange line in the graph. It directly follows from this that there is an advantage to be had by using more sensitive measurement methods that can detect weaker binding (which pushes the red curve to the left). Being able to detect these “lower complexity” molecules should increase the hit rate – the paradigm of fragment screening – now common terminology that is not used in the paper itself.


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