A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors
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.
Description
A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors - Journal of Medicinal Chemistry (ACS Publications)
%0 Journal Article
%1 Tanaka2011LEIFragmentsEH
%A Tanaka, Daisuke
%A Tsuda, Yusuke
%A Shiyama, Takaaki
%A Nishimura, Tamiki
%A Chiyo, Naoki
%A Tominaga, Yukio
%A Sawada, Nobuyuki
%A Mimoto, Tsutomu
%A Kusunose, Naoto
%D 2011
%J Journal of Medicinal Chemistry
%K fragment-based-screening lead-identification ligand-efficiency sEH soluble-epoxide-hydrolase
%N 3
%P 851-857
%R 10.1021/jm101273e
%T A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors
%U http://dx.doi.org/10.1021/jm101273e
%V 54
%X 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.
@article{Tanaka2011LEIFragmentsEH,
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. },
added-at = {2017-03-06T02:47:40.000+0100},
author = {Tanaka, Daisuke and Tsuda, Yusuke and Shiyama, Takaaki and Nishimura, Tamiki and Chiyo, Naoki and Tominaga, Yukio and Sawada, Nobuyuki and Mimoto, Tsutomu and Kusunose, Naoto},
biburl = {https://www.bibsonomy.org/bibtex/22f68d437e753fe3f6f01a74ff00a480e/salotz},
description = {A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors - Journal of Medicinal Chemistry (ACS Publications)},
doi = {10.1021/jm101273e},
eprint = {http://dx.doi.org/10.1021/jm101273e},
interhash = {59c57a37a1954663ea6ed242ca769da6},
intrahash = {2f68d437e753fe3f6f01a74ff00a480e},
journal = {Journal of Medicinal Chemistry},
keywords = {fragment-based-screening lead-identification ligand-efficiency sEH soluble-epoxide-hydrolase},
note = {PMID: 21192659},
number = 3,
pages = {851-857},
timestamp = {2017-03-06T02:47:40.000+0100},
title = {A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors},
url = {http://dx.doi.org/10.1021/jm101273e},
volume = 54,
year = 2011
}