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Discovery of promising B lymphocyte kinase inhibitors using structure-guided virtual screening.
- Source :
-
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2024 Aug; Vol. 42 (13), pp. 7054-7064. Date of Electronic Publication: 2023 Sep 08. - Publication Year :
- 2024
-
Abstract
- Tyrosine-protein kinase BLK, also known as B-cell lymphocyte kinase (BLK), is a non-receptor tyrosine kinase that is primarily expressed in B-cells. BLK plays a key role in B-cell signaling, particularly in B-cell development and maturation. The increased expression of BLK has been linked to various complex diseases, including autoimmune disorders, and specific malignancies of B cells, such as lymphomas and leukemias. Due to its significant involvement in B-cell signaling, BLK has emerged as a promising target for drug development, offering the potential for developing novel therapeutics to combat these diseases. Small molecule inhibitors of BLK hold great potential for therapeutic intervention; however, discovering potent and selective inhibitors remains challenging. Within this context, natural compounds hold significant potential as a valuable resource for discovering novel inhibitors of BLK. In the current study, a structure-based virtual screening of the IMPPAT 2 library was employed to identify promising candidates with potential as inhibitors of BLK. The control molecule for this study was the known BLK inhibitor, Dasatinib. After a multi-step filtering process, two molecules (Withanolide I and Mexogenin) demonstrated potential against BLK based on their superior binding affinity, ligand efficiency, and specific interaction. Interaction analysis of these compounds revealed several significant interactions with the active site residues of BLK. Both proposed molecules remained bound to the binding pocket of BLK, as indicated by the molecular dynamics (MD) simulation study. Taken together, these findings provide valuable insights for guiding future research endeavors and translational efforts in developing therapeutics for different complex diseases, such as autoimmune disorders, lymphomas, and leukemias.Communicated by Ramaswamy H. Sarma.
- Subjects :
- Humans
Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors
Agammaglobulinaemia Tyrosine Kinase metabolism
Agammaglobulinaemia Tyrosine Kinase chemistry
Protein Binding
Drug Discovery methods
Structure-Activity Relationship
Binding Sites
Ligands
Small Molecule Libraries chemistry
Small Molecule Libraries pharmacology
Drug Evaluation, Preclinical
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Molecular Docking Simulation
Molecular Dynamics Simulation
Subjects
Details
- Language :
- English
- ISSN :
- 1538-0254
- Volume :
- 42
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular structure & dynamics
- Publication Type :
- Academic Journal
- Accession number :
- 37688373
- Full Text :
- https://doi.org/10.1080/07391102.2023.2256397