Integrative computational approach to farnesyltransferase inhibition toward anti-liver cancer drug candidate from Syzygium cumini essential oils.

Abstract

Farnesyltransferase plays a critical role in the post-translational modification of mammalian proteins, including the Ras oncogene, which is strongly associated with cancer development. Essential oils from Syzygium cumini have demonstrated promising therapeutic effects, particularly in cancer treatment, potentially through the inhibition of farnesyltransferase activity. This study employed integrative computational approaches to investigate the anticancer potential of essential oils derived from S. cumini. Various compounds were screened for toxicity, biological activities, membrane permeability, gene expression profiles, and survival correlations were conducted to investigate cancer-associated properties. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate the binding interactions and stability of ligand-protein complexes involving farnesyltransferase. α-Humulene epoxide II exhibited antineoplastic activity, functioned as an apoptosis agonist, and inhibited cancer-related targets such as HIF1A and MMP9. Bornyl acetate showed potential as a JAK2 inhibitor. Both compounds demonstrated favorable membrane permeability, indicating high bioavailability and effective cellular uptake. Analysis of the farnesyltransferase (FNTB) gene revealed significantly higher expression in cancerous tissues and a positive correlation with pro-tumor immune cell infiltration. Molecular docking identified Tipifarnib as the strongest binder, serving as a positive control, while α-humulene epoxide II and bornyl acetate showed moderate to weaker binding affinities. However, MD simulations confirmed that both essential oil compounds exhibit binding stability comparable to that of Tipifarnib. Finally, α-humulene epoxide II and bornyl acetate from S. cumini exhibit favorable drug-like properties, high predicted safety margins, and a lack of organ-specific toxicity, underscoring their suitability for further drug development.