Theoretical Exploring Selective-Binding Mechanisms of JAK3 by 3D-QSAR, Molecular Dynamics Simulation and Free Energy Calculation

Frontiers in Molecular Biosciences
Jingyu ZhuJian Jin

Abstract

Janus kinase 3 (JAK3) plays a critical role in the JAK/STAT signaling pathway and has become an attractive selective target for the treatment of immune-mediated disorders. Therefore, great efforts have been made for the development of JAK3 inhibitors, but developing selective JAK3 inhibitors remains a great challenge because of the high sequence homology with other kinases. In order to reveal the selective-binding mechanisms of JAK3 and to find the key structural features that refer to specific JAK3 inhibition, a systematic computational method, including 3D-QSAR, molecular dynamics simulation, and free energy calculations, was carried out on a series of JAK3 isoform-selective inhibitors. Necessary pharmacodynamic structures and key residues involved in efficient JAK3-inhibition were then highlighted. Finally, 10 novel JAK3 inhibitors were designed, the satisfactory predicted binding affinity to JAK3 of these analogous demonstrated that this study may facilitate the rational design of novel and selective JAK3 inhibitors.

References

Jul 5, 1994·Proceedings of the National Academy of Sciences of the United States of America·M KawamuraJ R Ortaldo
Apr 27, 2000·Molecular Immunology·K Imada, W J Leonard
May 16, 2000·The Journal of Allergy and Clinical Immunology·W J Leonard, J X Lin
Dec 12, 2003·Nature Reviews. Immunology·Ke Shuai, Bin Liu
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 3, 2004·Nature Reviews. Drug Discovery·John J O'SheaPaul S Changelian
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
May 4, 2007·The Journal of Clinical Investigation·Wan-Wan Lin, Michael Karin
Mar 18, 2009·Immunological Reviews·Kamran GhoreschiJohn J O'Shea
Apr 2, 2011·Nature Reviews. Drug Discovery·Juswinder SinghAdrian Whitty
Dec 15, 2012·Nature Chemical Biology·Stefan KnappWilliam J Zuercher
Jan 8, 2013·Langmuir : the ACS Journal of Surfaces and Colloids·Somedatta Pal, Sanjoy Bandyopadhyay
Apr 2, 2013·Bioorganic & Medicinal Chemistry Letters·Saul Jaime-FigueroaCalvin Yee
Jan 15, 2014·Journal of Medicinal Chemistry·James D ClarkJean-Baptiste Telliez
Sep 14, 2014·Bioorganic & Medicinal Chemistry Letters·Gebhard ThomaHans-Günter Zerwes
Sep 30, 2014·Bioorganic & Medicinal Chemistry Letters·Javier de VicenteMichael Soth
Nov 27, 2015·American Journal of Physiology. Gastrointestinal and Liver Physiology·Silvio DaneseJean-Baptiste Telliez
Aug 27, 2018·Bioorganic & Medicinal Chemistry·Hisao HamaguchiTakayuki Inoue
Feb 1, 2019·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Anniina T VirtanenOlli Silvennoinen

❮ Previous
Next ❯

Software Mentioned

CoMFA Molecular Field Analysis
AMBER18
SYBYL
CoMFA
CoMSIA
SANDER
CDOCKER
Discovery studio
Gaussian09
SASA

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2022 Meta ULC. All rights reserved