Lipophilic ligand efficiency (LLE) is a parameter that integrates both potency and lipophilicity, serving as a measure of how effectively a ligand utilizes its lipophilicity to bind to a specific target . In the context of lead optimization, compounds are more likely to exhibit favorable in vivo performance if their potency can be enhanced without increasing their logP or logD values. While logP is commonly used to describe lipophilicity, it does not account for the ionization of functional groups at varying pH values, making it less reliable in biologically relevant conditions. In contrast, logD offers a more comprehensive view by considering ionization. Potency can be assessed through early-stage biochemical assays or more functionally relevant cell-based assays (equation ( )) .