In silico repurposing of clinically approved drugs as potential BRAF inhibitors: a pharmacophore-based virtual screening and experimental investigation
Abstract
The BRAF V600E mutation is a key oncogenic driver in multiple cancers. While FDA-approved BRAF inhibitors exist, their efficacy is often limited by drug resistance and adverse effects, necessitating the discovery of novel therapeutic agents. This study aimed to computationally repurpose clinically approved drugs as potential BRAF inhibitors. A ligand-based pharmacophore model was generated using five known BRAF inhibitors and validated to identify a robust three-feature hypothesis (one hydrogen bond acceptor and two aromatic rings). This model was used to screen the E-Drug3D database of FDA-approved drugs, yielding 666 initial hits. Subsequent structure-based virtual screening, molecular docking, and molecular dynamics simulations against both wild-type BRAF and BRAF V600E identified several promising candidates. Ticagrelor emerged as a top hit, demonstrating a stable binding mode and favorable molecular dynamics profile comparable to the reference inhibitor regorafenib. Experimental validation in colorectal cancer cell lines with varying BRAF status revealed that ticagrelor, along with other identified drugs like pioglitazone and nilotinib, exhibited significant anti-proliferative and pro-apoptotic effects. These findings suggest that ticagrelor is a promising repurposing candidate for BRAF inhibition and provide a foundation for overcoming current challenges in targeted cancer therapy.
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