Unlocking potential inhibitors for Bruton's tyrosine kinase through in-silico drug repurposing strategies

Abstract

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery.

Figure 1

(A) The protein–ligand interactions in a cartoon view (B) Surface view of BTK binding pocket occupied by the identified drugs and the reference molecule, Ibrutinib. The interacting residues are labelled when making hydrogen bonds within 3.5 Å during the interactions. Lower panels show the magnified view of the interactions with hydrogen bonds labelled.

Figure 2

2D diagrams of BTK interactions with (A) Eltrombopag (B) Alectinib (C) Ibrutinib.

Figure 3

Structural dynamics of BTK upon binding with Eltrombopag and Alectinib. (A) Time evolution of RMSD values during the simulation. (B) RMSF values of each residue in BTK during the simulation.

Figure 4

Structural compactness of BTK upon binding with Eltrombopag and Alectinib. (A) Time evolution of R_g values during the simulation. (B) Time evolution of SASA values during the simulation.

Figure 5

Hydrogen bond analysis. (A) Time evolution of intramolecular hydrogen bonds in BTK and (B) PDF distribution plot.

Figure 6

Time-evolution of intermolecular hydrogen bonds between BTK and elucidated drugs.

Figure 7

Principal component analysis of conformational projections of BTK and its complexes.

Figure 8

Free energy landscapes of (A) free BTK, (B) BTK-Eltrombopag and (C) BTK-Alectinib.