PART 1: Fragments as a Pre-Screen to Assess Target Drugability
This is the first in a series of blogs discussing the concept of using fragment screening to assess target drugability (also termed ligandability in the literature). The idea of using a fragment pre-screen to assess the likelihood of identifying a compound for lead optimization is not a new one. Because simple fragments have a higher probability of binding to targets than more complicated ligands (Hann et al., 2001), they are an ideal test-case for the drugability of a target. Furthermore, because fragment-space (MW < 200) is estimated at 10 orders of magnitude less than drug-size space (MW < 450), a small fragment library will sample chemical space much more efficiently than a library of larger compounds (Edfeldt et al., 2011). Applying this calculation to Zenobia’s Express-Zen-Core-288 compound fragment screen, for example, indicates using it as a drugability pre-screen would be like sampling ~2.88 trillion drug-sized molecules via high throughput screening.
Based on the Hann paper, this diagram was constructed to display how our different libraries demonstrate the principle of binding more easily due to small molecular weight.
Astra Zeneca recently reported the predictability of fragment screening for a successful drug discovery program (Edfeldt et al., 2011). Here, they did a retrospective analysis of 36 targets classifying them as highly druggable (multiple fragment hits with Kd < 0.1mM), medium drugability (fragment hits with Kd 0.1-1mM) and low drugability (fragment hits with Kd >1mM) based upon results from fragment screens. Targets classified as low drugability did not yield hits in a HTS campaign although two progressed forward via other lead sources. Medium drugability targets were largely successful as were high drugability targets although some yielded no hits. The lack of success in HTS for these medium and high drugability targets is not necessarily because the targets were undruggable. The targets that failed in HTS are known to have small binding pockets that would be more amenable to fragment binding than larger molecules. In these cases, the fragment hits could be progressed into lead optimization.
In our next installment, we will be discussing design principles for a fragment drugability screen.
To Recap: Studies by large pharmaceutical research companies prove that fragment screening is able to asses target drugability. Also, using smaller fragments greatly increases the efficiency of a screen, so screening Zenobia's Express-Zen-Core-288 would be equivalent to screening ~2.88 Trillion drug-sized molecules.
Edfeldt, F.N.B., Folmer, R.H.A., and Breeze, A.L. (2011). Fragment screening to predict druggability (ligandability) and lead discovery success. Drug Discov. Today 16, 284–287.
Hann, M.M., Leach, A.R., and Harper, G. (2001). Molecular complexity and its impact on the probability of finding leads for drug discovery. J Chem Inf Comput Sci 41, 856–864.