Identification of novel inhibitors targeting TIRAP interactions with BTK and PKC delta in inflammation through an in silico approach

Advanced computational tools focusing on protein-protein interaction (PPI) based drug development is a powerful platform to accelerate the therapeutic development of small lead molecules and repurposed drugs. Toll/interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP) and its interactions with other proteins in macrophages signalling are crucial components of severe or persistent inflammation. TIRAP activation through Bruton's tyrosine kinase (BTK) and Protein Kinase C delta (PKC delta) is essential for downstream inflammatory signalling. We created homology-based structural models of BTK and PKC delta in MODELLER 9.24. TIRAP interactions with BTK and PKC delta in its non-phosphorylated and phosphorylated states were determined by multiple docking tools including HADDOCK 2.4, pyDockWEB and ClusPro 2.0. Food and Drug Administration (FDA)-approved drugs were virtually screened through Discovery Studio LibDock and Autodock Vina tools to target the common TIR domain residues of TIRAP, which interact with both BTK and PKC at the identified interfacial sites of the complexes. Four FDA-approved drugs were identified and found to have stable interactions over a range of 100 ns MD simulation timescales. These drugs block the interactions of both kinases with TIRAP in silico. Hence, these drugs have the potential to dampen downstream inflammatory signalling and inflammation-mediated disease.

Automated summary

The use of advanced computational tools focusing on protein-protein interaction (PPI) has enabled the acceleration of drug development for small lead molecules and repurposed drugs. In this study, we investigated the interactions between Toll/interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP) and other proteins involved in macrophage signaling, specifically Bruton's tyrosine kinase (BTK) and Protein Kinase C delta (PKC delta). Through homology-based structural models and multiple docking tools, we identified FDA-approved drugs that have the potential to dampen downstream inflammatory signaling and inflammation-mediated diseases.