Occurrence of “Natural Selection” in Successful Small Molecule Drug Discovery

Published compounds from ChEMBL version 32 are used to
seek evidence
for the occurrence of “natural selection” in drug discovery.
Three measures of natural product (NP) character were applied, to
compare time- and target-matched compounds reaching the clinic (clinical
compounds in phase 1–3 development and approved drugs) with
background compounds (reference compounds). Pseudo-NPs (PNPs), containing
NP fragments combined in ways inaccessible by nature, are 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 untapped potential awaiting exploitation,
by applying nature’s building blocks“natural
intelligence”to drug design.