Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity.
The application of ligand efficiency metrics has been widely reported in the selection and optimization of fragments, hits and leads. In particular, optimization of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets.
Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physicochemical properties, are a practical means of estimating target 'druggability'. This is exemplified with 480 target–assay pairs from the primary literature. Across these targets, correlations between biological activity in vitro and physicochemical properties are generally weak, which shows that increasing activity by increasing physicochemical properties is not always necessary.
An analysis of 46 recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values and lipophilic ligand efficiency values for their target. Compared with 'only-in-class' oral drugs, only 1.5% of all molecules per target — on average — possess superior combined ligand efficiency and lipophilic ligand efficiency values.
Optimizing ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the ability to develop drug candidates.
The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.
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The authors thank N. Richmond (GlaxoSmithKline) for discussions on the derivation of efficiency metrics; G. Williams (Astex) for fruitful discussion on binding thermodynamics; R. Young (GlaxoSmithKline) for discussions on aromaticity and drug efficiency metrics; and AstraZeneca for providing access to the GVK BIO database.
The authors declare no competing financial interests.
Ligand efficiencies versus corresponding physical properties. (PDF 1260 kb)
Enthalpy and entropy ligand efficiencies versus properties. (PDF 2345 kb)
Mean, median and standard deviations of potencies, LE, LLE and LELP values for collections of oral drugs, Phase II compounds, hits and leads (PDF 361 kb)
- Spline fit
A statistical, numerical method for fitting a curve through a set of data points using a cubic polynomial.
The negative logarithm of activity in vitro in published papers: for example, half-maximal inhibitory concentration (IC50), inhibition constant (Ki) or effector concentration for half-maximum response (EC50) values.
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Hopkins, A., Keserü, G., Leeson, P. et al. The role of ligand efficiency metrics in drug discovery. Nat Rev Drug Discov 13, 105–121 (2014). https://doi.org/10.1038/nrd4163
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