title: Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds.
abstract: The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a compound is dependent on physicochemical properties such as molecular size, lipophilicity, and ionization state. However, much less is known regarding the relationship between ADMET and the molecular topology. In this study two descriptors related to the molecular topology have been investigated, the fraction of the molecular framework (f(MF)) and the fraction of sp(3)-hybridized carbon atoms (Fsp(3)). f(MF) and Fsp(3), together with standard physicochemical properties (molecular size, ionization state, and lipophilicity), were analyzed for a set of ADMET assays. It is shown that aqueous solubility, Caco-2 permeability, plasma protein binding, human ether-a-go-go-related potassium channel protein inhibition, and CYP3A4 (CYP = cytochrome P450) inhibition are influenced by the molecular topology. These findings are in most cases independent of the already well-established relationships between the properties and molecular size, lipophilicity, and ionization state.
authors.affiliation: Discovery Sciences, Computational Sciences, Computational Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. yidong@gmail.com
authors.forename: Yidong
authors.initials: Y
authors.lastname: Yang
authors.forename: Ola
authors.initials: O
authors.lastname: Engkvist
authors.forename: Antonio
authors.initials: A
authors.lastname: Llinàs
authors.forename: Hongming
authors.initials: H
authors.lastname: Chen
mesh_terms: D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D064420:Drug-Related Side Effects and Adverse Reactions; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012995:Solubility
chemical_list: D001798:Blood Proteins; D065692:Cytochrome P-450 CYP3A Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human