


Notwithstanding the recognition that an initial hit must be modified somewhat to get to the final product, 1-2 million compounds is a lot to screen, and one may wonder if there is an easier way that requires considerably fewer assays. The method of ‘evolving molecules’ that does this is known as fragment-based lead discovery, and works as follows. Imagine a hypothetical binding site with an affinity of 1 nM for a molecule of the form A-B-C. If there are 100 fragments that could serve to make A, B or C individually, the number of combinations is 100 x 100 x 100 = 106. However, if each of those fragments alone can bind with mM affinity, and we just have to find which 3, we only have to screen the 100 in the first instance. Based on this knowledge we can then search for whether the best answer is A-B-C, B-C-A and so on. Clearly the assembly of chemical fragments differs considerably from that of strings of letters, but the main message is clear: by using multiple steps of evolution (as also demonstrated in a chromatographic context elsewhere), including a selection step at each round, the number of individual assays required to find or evolve a potent molecule is massively reduced. In other words, given a robust assay and the necessary cheminformatics skills, fragment-based approaches make molecular discovery accessible to all laboratory budgets. Nowadays, many laboratories narrow the search space by effecting structural studies at each round, to assess exactly where each fragment binds and thus how to join them up optimally. The total number of individual (but skilfully selected) fragments used is usually in the low 100s. Some recent reviews of this include those by Rees et al., by Erlanson, by Hajduk & Greer, by Hubbard et al., by Jhoti et al.

In some ways, this is the molecular equivalent of the strategy discussed in the previous blog, where I looked at the inhibition of networks at multiple sites. However, in this case the fragment-based approaches are considerably better established. They also provide an unexpected twist on the ideas of evolution, a suitable topic to focus on as we approach Darwin Day.

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