The physicochemical challenges of designing multiple ligands.

Compounds designed to bind more than one target can provide a therapeutic benefit relative to highly target-selective ligands. The physicochemical properties of designed multiple ligands were found to be less druglike than those for preclinical compounds in general. These properties are controlled by the superfamily to which the targets belong and the lead discovery strategy that was followed. The properties for peptide G-protein-coupled receptor (GPCR) ligands were the least favorable for oral delivery, whereas transporter, monoamine GPCR, and oxidase ligands were the most druglike. The lead discovery strategy, framework combination or screening, exerts a profound influence on the property values. Combining the frameworks from two selective ligands often results in large, complex dual ligands, but druglike ligands can be achieved if the degree of framework overlap is maximized and the size of the selective ligands minimized. For some target combinations, a screening approach may provide a route to smaller, less complex leads.