title: Probing the links between in vitro potency, ADMET and physicochemical parameters.
abstract: A common underlying assumption in current drug discovery strategies is that compounds with higher in vitro potency at their target(s) have greater potential to translate into successful, low-dose therapeutics. This has led to the development of screening cascades with in vitro potency embedded as an early filter. However, this approach is beginning to be questioned, given the bias in physicochemical properties that it can introduce early in lead generation and optimization, which is due to the often diametrically opposed relationship between physicochemical parameters associated with high in vitro potency and those associated with desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) characteristics. Here, we describe analyses that probe these issues further using the ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds. Key findings include: first, that oral drugs seldom possess nanomolar potency (50 nM on average); second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose. These findings suggest that the perceived benefit of high in vitro potency may be negated by poorer ADMET properties.
authors.affiliation: The Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Road, Chatuchak, Bangkok 10900, Thailand. paul.gleeson@ku.ac.th
authors.forename: M Paul
authors.initials: MP
authors.lastname: Gleeson
authors.forename: Anne
authors.initials: A
authors.lastname: Hersey
authors.forename: Dino
authors.initials: D
authors.lastname: Montanari
authors.forename: John
authors.initials: J
authors.lastname: Overington
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D002627:Chemistry, Physical; D055808:Drug Discovery; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D011955:Receptors, Drug / Q000378:metabolism; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D004364:Pharmaceutical Preparations; D011955:Receptors, Drug