Generation of a Set of Simple, Interpretable ADMET Rules of Thumb

A set of simple, consistent structure-property guides have been determined from an analysis of a number of key ADMET assays run within GSK: solubility, permeability, bioavailability, volume of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using molecular properties that chemists intuitively know how to alter in a molecule, namely, molecular weight, logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the…