Computational and experimental insights into quinazoline derivatives: Targeting HOTAIR for therapeutic intervention...

Breast cancer which is the major cause of cancer deaths needs further innovative treatment methods to curb the weaknesses of the existing treatment methods. Quinazoline derivatives with an anticancer potential that seems to be highly promising are suggested to be used as targeted therapy in breast cancer. This paper explores the pharmacological role of 5,6,7,8-tetrahydroquinazoline derivatives in relation to the molecular interactions with HOTAIR (HOX transcript antisense intergenic RNA) which is a critical role in cancer metastasis. Computational studies such as molecular docking, molecular dynamics simulation was used in the research to evaluate binding affinity between identified quinazoline derivates and HOTAIR. Docking scores of the studied 25 compounds are between -7.4 to -9.4 kcal/mol with P14 demonstrating the best binding activity at -9.4 kcal/mol. Subsequent molecular dynamics simulations showed the structural stability of the complex between HOTAIR and P14 with a root mean square deviation (RMSD) range between 1.04 and 1.05 Å, the binding of the ligands to the RNA is also stable. MTT assays showed a dose-dependent reduction in the viability of the cells due to the cytotoxicity of the compounds in an in vitro setting. The obtained IC₅₀ results show that P14 was cytotoxic, given the obtained result of 57.73 µM. ADMET analysis revealed that P14 had decent bioavailability potential, but put certain concerns on toxicity, which has to be addressed by further in vitro and in vivo testing. These findings support the idea that quinazoline compounds and especially P14 have potential as therapeutic drugs against HOTAIR-mediated breast cancer and need to be investigated using preclinical models.