Beyond Size, Ionization State, and Lipophilicity: Influence of Molecular Topology on Absorption, Distribution, Metabolism, Excretion, and Toxicity for Druglike Compounds

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 (fMF) and the fraction of sp3-hybridized
carbon atoms (Fsp3). fMF and
Fsp3, 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.