Detailed Information

Cited 2 time in webofscience Cited 3 time in scopus
Metadata Downloads

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitorsopen access

Authors
Kumar, VikasParate, ShraddhaDanishuddinZeb, AmirSingh, PoojaLee, GihwanJung, Tae SungLee, Keun WooHa, Min Woo
Issue Date
30-Jun-2022
Publisher
FRONTIERS MEDIA SA
Keywords
SYK inhibitor; 3D QSAR; pharmacophore; autoimmune diseases; molecular docking; MD simulation
Citation
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v.12
Indexed
SCIE
SCOPUS
Journal Title
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
Volume
12
URI
https://scholarworks.bwise.kr/gnu/handle/sw.gnu/1148
DOI
10.3389/fcimb.2022.909111
ISSN
2235-2988
Abstract
Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (Delta G), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.
Files in This Item
There are no files associated with this item.
Appears in
Collections
수의과대학 > Department of Veterinary Medicine > Journal Articles

qrcode

Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.

Related Researcher

Researcher Jung, Tae Sung photo

Jung, Tae Sung
수의과대학 (수의학과)
Read more

Altmetrics

Total Views & Downloads

BROWSE