Dynamic modeling of human 5-lipoxygenase-inhibitor interactions helps to discover novel inhibitors

Yiran Wu; Chong He; Yang Gao; Shan He; Ying Liu; Luhua Lai

doi:10.1021/jm201497k

Dynamic modeling of human 5-lipoxygenase-inhibitor interactions helps to discover novel inhibitors

J Med Chem. 2012 Mar 22;55(6):2597-605. doi: 10.1021/jm201497k. Epub 2012 Mar 1.

Authors

Yiran Wu¹, Chong He, Yang Gao, Shan He, Ying Liu, Luhua Lai

Affiliation

¹ BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

PMID: 22380511
DOI: 10.1021/jm201497k

Abstract

Human 5-lipoxygenase (5-LOX) is one of the key anti-inflammatory drug targets due to its key role in leukotrienes biosynthesis. We have built a model for the active conformation of human 5-LOX using comparative modeling, docking of known inhibitors, and molecular dynamics simulation. Using this model, novel 5-LOX inhibitors were identified by virtual screen. Of the 105 compounds tested in a cell-free assay, 30 have IC(50) values less than 100 μM and 11 less than 10 μM with the strongest inhibition of 620 nM. Compounds 4, 7, and 11 showed strong inhibition activity in the human whole blood (HWB) assay with IC(50) values of 8.6, 9.7, 8.1 μM, respectively. Moreover, compounds 4 and 7 were also found to inhibit microsomal prostaglandin E synthase (mPGES)-1 with micromolar IC(50) values, similar to licofelone, a dual functional inhibitor of 5-LOX/mPGES-1. The compounds reported here provide new scaffolds for anti-inflammatory drug design.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Arachidonate 5-Lipoxygenase / blood
Arachidonate 5-Lipoxygenase / chemistry*
Cell-Free System
Databases, Factual
Dinoprostone / blood
Humans
Intramolecular Oxidoreductases / antagonists & inhibitors
Intramolecular Oxidoreductases / blood
Leukotriene B4 / blood
Lipoxygenase Inhibitors / chemistry*
Lipoxygenase Inhibitors / pharmacology
Microsomes / enzymology
Molecular Dynamics Simulation*
Prostaglandin-E Synthases
Protein Binding
Protein Conformation
Pyrroles / chemistry
Pyrroles / pharmacology
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / chemistry
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Lipoxygenase Inhibitors
Pyrroles
Recombinant Proteins
Leukotriene B4
Arachidonate 5-Lipoxygenase
Intramolecular Oxidoreductases
PTGES protein, human
Prostaglandin-E Synthases
Dinoprostone
licofelone