New antagonists of toll-like receptor 7 discovered through 3D ligand-based virtual screening

被引：0

作者：

Urban Švajger

Žiga Horvat

Damijan Knez

Primož Rožman

Samo Turk

Stanislav Gobec

机构：

[1] Blood Transfusion Centre of Slovenia,Faculty of Pharmacy

[2] University of Ljubljana,undefined

来源：

Medicinal Chemistry Research | 2015年 / 24卷

关键词：

Virtual screening; Immunomodulators; Toll-like receptor ligands; Antagonists;

D O I：

暂无

中图分类号：

学科分类号：

摘要：

Toll-like receptor (TLR) 7 has an important role in immune activation processes and represents an emerging drug discovery target for the development of immunomodulators. Three-dimensional similarity-based virtual screening was performed using the Rapid Overlay of Chemical Structures software (vROCS version 3.1.1. OpenEye Scientific Software, Santa Fe, NM. http://www.eyesopen.com) to search for potential ligands of TLR7. Six new compounds with three new chemical scaffolds were discovered as initial hit antagonists of TLR7, with IC50 values in the micromolar range, as determined by reporter assays. With only the imidazoquinolines described as small-molecule TLR7 antagonists to date, the new chemotypes described in this report represent an important starting point for the development of drug candidates for treatment of autoimmune diseases.

引用

页码：362 / 371

页数：9

共 66 条

[1]

Barrat FJ(2005)Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus J Exp Med 202 1131-1139

[2]

Blasius AL(2010)Assessing the performance of OMEGA with respect to retrieving bioactive conformations Intracellular toll-like receptors immunity 32 305-315

[3]

Beutler B(2003)A fast method of molecular shape comparison: a simple application of a Gaussian description of molecular shape J Mol Graph Model 21 449-462

[4]

Bostrom J(1996)Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database J Comput Chem 17 1653-1666

[5]

Greenwood JR(2010)Immunostimulatory potential of silencing RNAs can be mediated by a non-uridine-rich toll-like receptor 7 motif J Chem Inf Model 50 572-584

[6]

Gottfries J(2011)Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists Nucleic Acid Ther 21 201-214

[7]

Grant JA(2007)Meso-unsubstituted iron corrole in hemoproteins: remarkable differences in effects on peroxidase activities between myoglobin and horseradish peroxidase Nat Med 13 552-559

[8]

Gallardo MA(2009)Simple and efficient Copper(I)-catalyzed access to three versatile aminocoumarin-based scaffolds using isocyanoacetate J Am Chem Soc 131 15124-15125

[9]

Pickup BT(2011)Imiquimod applied topically: a novel immune response modifier and new class of drug Adv Synth Catal 353 918-924

[10]

Hawkins PC(1999)Toll-like receptors Int J Immunopharmacol 21 1-14

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