Following on from his earlier papers (e.g. ADMET rules of thumb for candidate drug design), Gleeson’s most recent publication in Nature Reviews|Drug Discovery details a now familiar tale of physicochemical woe associated with the failure of many medicinal chemistry programmes to focus adequately on properties other than target affinity. Once again arguing that an over-reliance on targeting high potency in order to minimize the clinical dose and risk of toxicity related attrition (see now classic papers & citing works by Leeson and Hann) has continually seduced medicinal chemists away from ‘drug-like space’. These are points which in themselves are worthy of further emphasis, but of particular interest in this case is the origin of the data in the ChEMBL database, a publicly accessible database of targets and drugs compiled by the European Bioinformatics Institute (EBI). Whilst some of the available data are incomplete (and the authors acknowledge the limitations in their analyses) this database is an important and often under-utilized source of information and is worthy of wider attention. In contrast to many of the physicochemical analyses published to date, all the ChemBL source information is freely accessible for others to validate and/or challenge. The database contains over half a million compounds (stored as 2D structures), with accompanying in vitro biological data and calculated properties.
For this analysis, the authors calculated an ADMET score (i.e. the deviation from oral drug space as defined by AlogP and molecular mass) to characterize the data set. The plot below shows 1791 oral drugs colour-coded according to their ADMET score (on the left), and then (on the right) the same drugs compared with the scores for the total content of the ChEMBL database (approximately 200k compounds). A greater deviation from oral drug space is observed in the latter case (14% of drugs have ADMET scores >2 compared with 39% of ChEMBL molecules).
- Average oral drug potency is approx 50 nM (Another clear observation was that 8% of oral drugs have both mol mass > 400 and AlogP > 4, compared to 30% of all ChEMBL molecules and 41% of ChEMBL molecules with nanomolar potency).
- The majority of oral drugs have off-target pharmacological activities (This analysis was clearly complicated by any intentional poly-pharmacology). The graphic below shows, for 392 oral drugs, N = number of off-target hits with reported potencies ≤ 1 µM (i.e. only 29% in the N=0 segment are totally selective) :
- There was no clear relationship between in vitro potency and therapeutic dose (which is perhaps unsurprising given the numerous additional factors involved).
Whilst the points made in the paper mainly serve to reinforce the conclusions of earlier publications, they nonetheless highlight the importance, and usefulness, of open-source information sources and the prospect of their more widespread utility in future.