| Affiliation: | 1. Computational Chemistry, H. Lundbeck A/S, Ottiliavej 9, 2300 Valby, Copenhagen, Denmark;2. Physical Chemistry, Cyprotex Discovery Limited, Alderley Park, Nether Alderley, Cheshire, SK10 4TG UK;3. Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ UK
DMPK, UCB Celltech, Branch of UCB Pharma S.A., 208 Bath Road, Slough, Berkshire, SL1 3WE UK;4. Drug Design, LEO Pharma A/S, Industriparken 55, 2550 Ballerup, Denmark |
| Abstract: | Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Å2 was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R2=0.92) with an experimental measure of hydrogen bond donor potential, Δlog Poct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility. |
