title: Generation of a set of simple, interpretable ADMET rules of thumb.
abstract: A set of simple, consistent structure-property guides have been determined from an analysis of a number of key ADMET assays run within GSK: solubility, permeability, bioavailability, volume of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using molecular properties that chemists intuitively know how to alter in a molecule, namely, molecular weight, logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the analyses reported herein that almost all ADMET parameters deteriorate with either increasing molecular weight, logP, or both, with ionization state playing either a beneficial or detrimental affect depending on the parameter in question. This study re-emphasizes the need to focus on a lower molecular weight and logP area of physicochemical property space to obtain improved ADMET parameters.
authors.affiliation: Computational and Structural Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom. paul.x.gleeson@gsk.com
authors.forename: M Paul
authors.initials: MP
authors.lastname: Gleeson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D004345:Drug Industry; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D010599:Pharmacokinetics; D017149:Private Sector; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D004364:Pharmaceutical Preparations