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Biomedical subjects

Richard Morphy

Publications and source records attributed to Richard Morphy.

4 recordsLinked to original sources
PubMed2006

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.

Carrier Proteins↗
PubMed2006

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.

Carrier Proteins↗
PubMed2004

From magic bullets to designed multiple ligands.

Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. Rational approaches in which structural features from selective ligands are combined have produced designed multiple ligands that span a wide variety of targets and target classes. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. An analysis of literature examples reveals trends and insights that might help medicinal chemists discover the next generation of these types of compounds.

Chemistry, Pharmaceutical↗