ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
0/0

The Nature of Ligand Efficiency

preprint
submitted on 28.10.2018 and posted on 29.10.2018 by Peter Kenny

Ligand efficiency is a widely used design parameter in drug discovery. It is calculated by scaling affinity by molecular size and has a nontrivial dependency on the concentration unit used to express affinity that stems from the inability of the logarithm function to take dimensioned arguments. Consequently, perception of efficiency varies with the choice of concentration unit and it is argued that the ligand efficiency metric is not physically meaningful nor should it be considered to be a metric. The dependence of ligand efficiency on the concentration unit can be eliminated by defining efficiency in terms of sensitivity of affinity to molecular size and this is illustrated with reference to fragment-to-lead optimizations. An alternative to ligand efficiency for normalization of affinity with respect to molecular size is presented. Group efficiency and fit quality are also examined in detail from a physicochemical perspective. The importance of examining relationships between affinity and molecular size directly is stressed throughout this study.

History

Email Address of Submitting Author

pwk.pub.2008@gmail.com

Institution

Berwick-on-Sea

Country

Trinidad and Tobago

ORCID For Submitting Author

0000-0002-3105-2909

Declaration of Conflict of Interest

No conflict of interest

Version Notes

Initial submission

Exports