Asset Details
Do you wish to reserve the book?
Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR
Do you wish to request the book?
Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Structure-Based Virtual Screening of Ultra-Large Library Yields Potent Antagonists for a Lipid GPCR
2020
Overview
Cysteinyl leukotriene G protein-coupled receptors, CysLT1R and CysLT2R, regulate bronchoconstrictive and pro-inflammatory effects and play a key role in allergic disorders, cardiovascular diseases, and cancer. CysLT1R antagonists have been widely used to treat asthma disorders, while CysLT2R is a potential target against uveal melanoma. However, very few selective antagonist chemotypes for CysLT receptors are available, and the design of such ligands has proved to be challenging. To overcome this obstacle, we took advantage of recently solved crystal structures of CysLT receptors and an ultra-large Enamine REAL library, representing a chemical space of 680 M readily available compounds. Virtual ligand screening employed 4D docking models comprising crystal structures of CysLT1R and CysLT2R and their corresponding ligand-optimized models. Functional assessment of the candidate hits yielded discovery of five novel antagonist chemotypes with sub-micromolar potencies and the best Ki = 220 nM at CysLT1R. One of the hits showed inverse agonism at the L129Q constitutively active mutant of CysLT2R, with potential utility against uveal melanoma.
Publisher
MDPI AG,MDPI
Subject
/ Drug Evaluation, Preclinical
/ Energy
/ GPCR
/ Humans
/ Ligands
/ Lipids
/ Melanoma
/ Molecular Docking Simulation
/ Mutation
/ Receptors, Leukotriene - chemistry
/ Receptors, Leukotriene - metabolism
/ Small Molecule Libraries - chemistry
/ Small Molecule Libraries - metabolism
/ Small Molecule Libraries - pharmacology
