Drug Discovery
Exploring the horizons of small molecule drug
discovery the evolution and application of the ideal fragment library
With the pharmaceutical industry facing unprecedented challenges in small molecule drug discovery, this paper argues that, with the correct design of the fragment library, Fragment-Based Drug Discovery has emerged as a complementary strategy to High Throughput Screening.
O
ver the last decade, fragment screening has emerged as a complementary strategy to high throughput screening (HTS) and Fragment Based Drug Discovery (FBDD) has gained wide acceptance within the pharmaceutical and biotechnology sectors, with a number of frag- ments progressed into lead series and on to clini- cal candidates1-4. Initial hits are identified by screening small libraries typically of 500-2,000 fragments of low molecular weight (MW 100- 300Da) against a target. Fragments bind with low
affinity (KD values in the high micromolar to mil- limolar range) and are, therefore, screened at high concentration using biophysical techniques such as NMR, x-ray crystallography and surface plas- mon resonance (SPR). Historically, HTS libraries have been populated by ‘drug-like’ molecules, mostly chosen to comply with Lipinski’s rule of five5,6. However, these mol- ecules tend to be large and lipophilic and thus are difficult to develop into potent compounds with- out reducing their ‘drug-likeness’. Poor absorp-
Drug Discovery World Winter 2011/12
tion, distribution and metabolism characteristics caused by high molecular weight and lipophilicity are major reasons for attrition of lead candidates. Hit rates from HTS screens are invariably low, as complex screening compounds form mismatches with receptors due to suboptimal interactions or steric clashes. Fragments are simpler and smaller so are more likely to fit into the binding site with- out these unfavourable interactions7. Fragments typically bind with lower affinity to the target sites than larger drug-like molecules that can form many more interactions, but the binding efficiency per atom is as high or higher. Fragment hits can then be readily optimised into potent leads by syn- thesising larger compounds that pick up addition- al target-ligand interactions resulting in improved affinity for the target, while still maintaining ‘drug-likeness’. Astex Pharmaceuticals reports that it is nearly always possible to obtain nM lead compounds through the synthesis of 20-100 ana- logues starting from the fragment hit for a wide range of target classes8.
By Dr David Myszka and Dr Jane Paul
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