The concept of ligand potency is briefly discussed here as well as why this is still a challenge for its complete comprehension. In this context, we explain also the meaning of ligand efficiency (LE), which has been greeted with both enthusiasm and criticism among the drug design audience. A full understanding of LE requires the complex interpretation of the potency concept presenting the uncertainty similar to this of the Zeno paradox. In reality, the efficiency of LE is caused by the high degree of preference for slim pharma drug candidates.

Background: Potency is the broadest available biological activity data type. In turn, Ligand Efficiency (LE) is a molecular descriptor that probes the ratio of potency vs Heavy Atom Count (HAC), which emphasizes low HAC more than potency and thus has drawbacks as an estimator of drug candidates. The objective was to design a novel transform to probe potency and HAC interaction in which potency and HAC would be balanced more evenly. Methods: In this study, potency data of ChEMBL, PubChem, FDA approvals and drug (fragments) were analysed. A novel descriptor, a product of the pAC50 value with HAC, multiplicative or Product Ligand Efficiency (PLE) was designed and tested. Results: In particular PLE was compared with pAC50 and LE vs the HAC statistics for different series of ligands. This indicated that PLE is an informative estimator that can be used to recognize the potential of drugs. PLE has a maximum value in the range around 30-50 HAC. Conclusion: Drug design is a complex problem. Similarly, to drug-likeness, LE prefers small molecules. This makes LE a tool serendipitously improving drug likeness. In this context, LE performs unexpectedly well even despite the uncertainty of its physical meaning. PLE is a more evenly balanced estimator whose physical meaning is the Minimum Inhibitory Concentration (MIC).

Ligand efficiency (LE) is a molecular descriptor that probes the ratio of potency vs. heavy atom count (HAC). As an estimator of drug candidates, LE emphasizes a low heavy atom count more than potency. The objective was to design a novel transform where potency and the HAC would be balanced more evenly. A series of novel descriptors SCORE were defined to evaluate the co-influence of potency and the HAC. In particular, the product ligand efficiency (PLE) was designed and tested using the data of the ChEMBL, PubChem as well as the selected series of drugs and drug-fragments.