Journal
DRUG DISCOVERY TODAY
Volume 21, Issue 5, Pages 712-717Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.drudis.2016.02.005
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Funding
- NIH [1R01GM094551]
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Key to the pharmaceutical utility of certain macrocyclic drugs is a 'chameleonic' ability to change their conformation to expose polar groups in aqueous solution, but bury them when traversing lipid membranes. Based on analysis of the structures of 20 macrocyclic compounds that are approved oral drugs, we propose that good solubility requires a topological polar surface area (TPSA, in angstrom(2)) of >= 0.2 x molecular weight (MW). Meanwhile, good passive membrane permeability requires a molecular (i.e., 3D) PSA in nonpolar environments of <= 140 angstrom(2). We show that one or other of these limits is almost invariably violated for compounds with MW > 600 Da, suggesting that some degree of chameleonic behavior is required for most high MW oral drugs.
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