In silico repurposing of FDA approved drug compounds for dual targeting of HER2 and EGFR

Title : In silico repurposing of FDA approved drug compounds for dual targeting of HER2 and EGFR

Abstract:

Background 
Dysregulated HER2 and EGFR signalling promote tumor growth and therapeutic resistance in breast, gastroesophageal and lung cancers. Tyrosine kinase inhibitors (TKIs) such as lapatinib have been clinically approved; however, their long-term benefit is limited by resistance mutations, bypass signalling and adverse drug reactions. In silico drug repurposing offers a cost-effective route to identify new dual-targeted anticancer candidates. 
Objective 
To identify FDA-approved drug compounds capable of dual inhibition of HER2 and EGFR using computational screening techniques. 
Methodology 
A total of 2,465 drug bank FDA-approved compounds were filtered for drug-likeness using Lipinski, veber, ghose and egan filters to obtain 453 drug-like compounds. auto dock Vina v1.2.3 was used for docking-based screening of the library against the inactive-state HER2 (PDB: 3PP0, 2.25 Å) and EGFR (PDB: 3W32, 1.80 Å), which had been prepared in auto dock Tools v1.5.7. The top 20 hits underwent ADMET prediction in ADMETlab 3.0 and detailed protein-ligand interaction analysis in Discovery Studio Visualizer and PyMOL v3.1.0. 
Results 
The mean library binding affinities were −7.70 kcal/mol (HER2) and −8.05 kcal/mol (EGFR) while Lapatinib (positive control) showed −11.76 kcal/mol on both kinases. Dolutegravir had high binding affinities for HER2 (−12 kcal/mol) and EGFR (−11.25 kcal/mol) while interacting with the gatekeeper residues of both targets. Niraparib demonstrated stable interaction networks with receptor-deactivating residues and had balanced binding affinities for both 
HER2 (-9.85 kcal/mol) and EGFR (−10 kcal/mol). Their ADMET properties were favorable.
Conclusion 
Dolutegravir and niraparib are promising dual-target candidates, providing a foundation for molecular dynamics simulations, experimental validation and further optimization for dual targeting of HER2 and EGFR in cancer therapy. 
Keywords: HER2, EGFR, repurposing, in silico, docking.

Biography:

Mr. Edward Tichivangani, a final-year student in the Biotechnology and Bioinformatics programme at Midlands State University, stated that his research focuses on the in silico repurposing of FDA-approved compounds for the dual targeting of HER2 and EGFR. He expressed his gratitude for the consideration of his application and mentioned that he looked forward to being part of the initiative.