Virtual Screening through Molecular Docking Analysis to Identify Potential Natural Inhibitor(s) of Lyn Tyrosine Kinase- An In-silico Approach

Breast cancer on becoming one of the leading cancer types, emerged as an important barrier in increasing life expectancy of the overall population. In the current study, some compounds were screened based on literature survey for the identification of natural bioactive compounds as potential inhibitors of Lyn tyrosine kinase. Therefore, a multi-step molecular docking was carried out using AutoDock embedded in the MGL Tools. After initial screening, molecules having a higher docking score and binding free energy compared to Tamoxifen were considered for further assessment. Some already known synthetic lyn tyrosine kinase inhibitor have been used for better understanding of the comparative study. Based on in silico Lipinski filter analysis, toxicity prediction, pharmacokinetic analysis, four compounds were proposed to be promising inhibitors of Lyn tyrosine kinase. Furthermore, the binding interactions of all proposed inhibitors of Lyn showed strong ligand efficiency in terms of energy score obtained with the help of molecular modelling analyses. Hence, the proposed compounds out of which three are bioactive compounds might be taken forward as potential next-generation Lyn kinase inhibitors for managing Lyn associated breast cancer after experimental authentication.

Lipid-based and protein-based interactions synergize transmembrane signaling stimulated by antigen clustering of IgE receptors

Antigen (Ag) crosslinking of immunoglobulin E–receptor (IgE-FcεRI) complexes in mast cells stimulates transmembrane (TM) signaling, requiring phosphorylation of the clustered FcεRI by lipid-anchored Lyn tyrosine kinase. Previous studies showed that this stimulated coupling between Lyn and FcεRI occurs in liquid ordered (Lo)-like nanodomains of the plasma membrane and that Lyn binds directly to cytosolic segments of FcεRI that it initially phosphorylates for amplified activity. Net phosphorylation above a nonfunctional threshold is achieved in the stimulated state but not in the resting state, and current evidence supports the hypothesis that this relies on Ag crosslinking to disrupt a balance between Lyn and tyrosine phosphatase activities. However, the structural interactions that underlie the stimulation process remain poorly defined. This study evaluates the relative contributions and functional importance of different types of interactions leading to suprathreshold phosphorylation of Ag-crosslinked IgE-FcεRI in live rat basophilic leukemia mast cells. Our high-precision diffusion measurements by imaging fluorescence correlation spectroscopy on multiple structural variants of Lyn and other lipid-anchored probes confirm subtle, stimulated stabilization of the Lo-like nanodomains in the membrane inner leaflet and concomitant sharpening of segregation from liquid disordered (Ld)-like regions. With other structural variants, we determine that lipid-based interactions are essential for access by Lyn, leading to phosphorylation of and protein-based binding to clustered FcεRI. By contrast, TM tyrosine phosphatase, PTPα, is excluded from these regions due to its Ld-preference and steric exclusion of TM segments. Overall, we establish a synergy of lipid-based, protein-based, and steric interactions underlying functional TM signaling in mast cells.

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a−/− mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a−/− basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a−/− Lyn−/− showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a−/− hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.