title: Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs.
abstract: 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 Å(2)) of ≥0.2×molecular weight (MW). Meanwhile, good passive membrane permeability requires a molecular (i.e., 3D) PSA in nonpolar environments of ≤140Å(2). We show that one or other of these limits is almost invariably violated for compounds with MW>600Da, suggesting that some degree of chameleonic behavior is required for most high MW oral drugs.
authors.affiliation: Department of Chemistry, Boston University, Boston, MA, USA. Electronic address: whitty@bu.edu.
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitty
authors.affiliation: Department of Chemistry, Boston University, Boston, MA, USA.
authors.forename: Mengqi
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Chemistry, Boston University, Boston, MA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Viarengo
authors.affiliation: Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Beglov
authors.affiliation: Acpharis Inc., Holliston, MA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Hall
authors.affiliation: Department of Chemistry, Boston University, Boston, MA, USA; Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, USA. Electronic address: Vajda@bu.edu.
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
mesh_terms: D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008970:Molecular Weight
chemical_list: D047028:Macrocyclic Compounds