Computational analysis of Piper spp.-derived natural products as anti-cancer potential through targeting aurora kinase A

Aurora kinase A (AURKA) overexpression correlates with increased tumor grade, resistance to chemotherapy, and poor breast cancer prognosis. Targeting AURKA is a promising way to suppress breast cancer development. Several species of the genus Piper have been famously used as anti-cancer agents due to their bioactive compounds. The bioactive compounds were carefully selected based on their toxicity using computational methods via the SwissADME and ProTox 3.0 web servers. The target protein prediction and network analysis toward cancer cells were then performed using the SwissTargetPrediction webserver, STRING database version 12.0, and the Cancer Hallmarks webserver. Analysis of bioactive compounds against target protein in breast cancer was performed using UALCAN, GEPIA and TIMER 2.0. The validation structure was analyzed with SAVESv6.1 webserver and ProSA-web. Molecular docking was performed using PyRx 0.8. The molecular dynamics simulation was performed using YASARA. The result showed that epi-γ-eudesmol, guaiol acetate, γ-cadinene, and safrole were selected as drug candidates. The analysis showed that guaiol acetate had the lowest acute toxicity, making it the most favorable candidate. Based on intersection analysis, AURKA was identified as most likely therapeutic target for breast cancer therapy. In addition, AURKA was known to have higher upregulation in cancer cells which leads to poor prognosis. Regarding the immune system, AURKA significantly promotes pro-tumor immune cell infiltration and suppresses anti-tumor immune cells. Structural validation analysis showed acceptable stereochemical quality. The molecular docking results showed that guaiol acetate and AT9283 bind to the same catalytic site around the highly conserved Asp-Phe-Gly motif and the ATP-binding pocket. The molecular dynamics analysis showed that AURKA-guaiol acetate complex exhibited lower structural stability and mobility than AURKA-AT9283 complex. In addition, AURKA-guaiol acetate complex exhibited less compact structure and greater fluctuations. In conclusion, guaiol acetate shows potential as a cancer drug candidate as it has lower toxicity and evident targeted cancer activity. Guaiol acetate may mimic AT9283 as an AURKA-targeted inhibitor, although it has slightly lower potency.