jm0603015_si_001.pdf (42.91 kB)
The Physicochemical Challenges of Designing Multiple Ligands
journal contribution
posted on 2006-08-10, 00:00 authored by Richard Morphy, Zoran RankovicCompounds 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.