ADMET rules of thumb II: A comparison of the effects of common substituents on a range of ADMET parameters.
A systematic analysis of data generated in key in vitro assays within GSK has been undertaken to identify what impact a range of common substituents have on a range of ADMET parameters. These include; P450 1A2, 2C9, 2C19, 2D6 and 3A4 inhibition, hERG inhibition, phosphate buffer solubility and artificial membrane permeability. We do this by identifying all matched molecular pairs, differing by the replacement of a hydrogen atom with a list of predefined substituents. For each substituent we calculate the mean difference in the ADMET parameter for all the matched molecular pairs identified, making a statistical assessment of the difference, as well as assessing the diversity for each example to ensure that the results can be generalized. We also relate the change in activity observed for each substituent to differences in their molecular properties in an effort to identify any structural alerts.
Gleeson
Paul
P
GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK. paul.gleeson@ku.ac.th
Bravi
Gianpaolo
G
Modi
Sandeep
S
Lowe
Daniel
D
D002463:Cell Membrane Permeability; D020650:Combinatorial Chemistry Techniques; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; 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 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D004364:Pharmaceutical Preparations; D020033:Protein Isoforms; D003577:Cytochrome P-450 Enzyme System