The Influence of Target Family and Functional Activity on the Physicochemical Properties of Pre-Clinical Compounds

Abstract

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.

The role of ligand efficiency metrics in drug discovery

“…Achieving high LLE values in optimised molecules is therefore more likely when starting with low cLogP leads (ideally <3). These observations on newer drugs and on current practices contrast with earlier literature studies, 24,25,51 largely pre-dating the application of ligand efficiency concepts, in which lipophilicity, on average, increased during optimisation. We conclude that optimisation of lipophilic ligand efficiencies will guide projects towards potent molecules with lowered lipophilicity, which will in turn improve the developability of emerging candidate compounds.…”

“…The physical property trends across the target classes in Figure 4b are consistent with other studies. 17,20,51,60 The least druggable target classes, on both property and were progressed into X-ray crystallography. 56 The phenol, 2, has low LE, 0.26 kcal/mol/heavy atom showing that its binding affinity (790M by isothermal titration calorimetry) is suboptimal.…”

Modeling Promiscuity Based on in vitro Safety Pharmacology Profiling Data

“…As the profiling panel contains a large number of GPCR targets, previously published work suggested to find such privileged substructures in promiscuous compounds. [22][23][24] Other substructures were checked, but were not significantly prominent in one group or the other. Carboxylic acids show a high selectivity that is probably due to the possible negative charge of the carboxylate group which can lead to unfavorable interactions with most targets of the current in vitro safety panel.…”

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…In other words, less complex molecules are more prone to bind to multiple proteins due to the lower probability of a mismatch between ligand and the proteins of interest. Along the same lines, Morphy's analysis of Organon's SCOPE database revealed a clear correlation between size and selectivity [15], supporting the hypothesis that the inherent simplicity of small molecules favours non-selective binding events [16]. Moreover, there is ample experimental support for a higher hit rate for fragments in multitarget screening with respect to the larger compounds typically screened in high throughput screening (HTS).…”