Occurrence of ‘Natural Selection’ in Successful Small Molecule Drug Discovery

A highly curated dataset of published compounds from ChEMBL version 32 is used to seek evidence for the occurrence of ‘natural selection’ in drug discovery. Three complementary measures of natural product (NP) character were applied, to compare time- and target-matched compounds reaching the clinic (Clinical compounds in phase 1-4 development) with background compounds (Reference compounds). Pseudo-natural products (PNPs), containing NP fragments combined in ways inaccessible by Nature, are rapidly increasing over time, reaching 67% of Clinical compounds first disclosed since 2010. PNPs are 54% more likely to be found in post-2008 Clinical versus Reference compounds. The majority of target classes show increased Clinical compound NP character versus their Reference compounds. Only 176 NP fragments appear in >1000 Clinical compounds published since 2008, yet these make up on average 63% of the Clinical compound’s core scaffolds. There is huge untapped potential awaiting exploitation, by applying Nature’s building blocks - ‘Natural Intelligence’ - to drug design.