The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds.
The target families of greatest interest in drug discovery can be differentiated on the basis of the physicochemical properties of their pre-clinical ligands. The ligands for peptidergic targets, such as peptide GPCRs and integrin receptors, possess significantly higher median property values than those for aminergic targets, such as monoamine transporters and GPCRs. The ligands for peptide GPCRs were found to be less efficient, in terms of their binding energy per unit of molecular weight or lipophilicity, than ligands for monoamine GPCRs. The changes in the property values during the optimization process were found to vary only slightly across the target families, with the main determinant of the drug-likeness of the optimized compounds being the profile of the starting compounds. Agonists for monoamine GPCRs, opioid receptors and ion channels were typically smaller and less lipophilic than the antagonists, but there was no difference between the agonists and the antagonists for peptide GPCRs and nuclear receptors.
Morphy
Richard
R
Medicinal Chemistry Department, Organon Laboratories, Newhouse, Lanarkshire ML1 5SH, UK. r.morphy@organon.co.uk