A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors

TLDR

Ligand efficiency is widely used in fragment‑based drug discovery to assess fragment compounds and guide the selection of lead‑like molecules with favorable size and lipophilicity. The study proposes a practical ligand‑efficiency–guided methodology for lead generation. The authors applied ligand‑efficiency indices during a virtual‑screening–initiated lead‑generation study targeting soluble epoxide hydrolase inhibitors. By selecting a weak inhibitor with high ligand efficiency, a hit‑to‑lead medicinal chemistry campaign produced a more potent, ADMET‑clean, lead‑like compound that retained high ligand efficiency, and retrospective analysis confirmed the validity of the ligand‑efficiency–guided triage.

Abstract

Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.