Abstract <p>Chagas disease (CD), caused by the kinetoplastid protozoan <i>Trypanosoma cruzi</i>, remains a major neglected tropical illness with limited therapeutic options. Natural products have historically provided structurally diverse scaffolds that serve as privileged templates in medicinal chemistry. Candimine (Cnd), an alkaloid isolated from <i>Hippeastrum escoipense</i> (Amaryllidaceae), has recently emerged as a promising compound with activity against <i>T. cruzi</i>. Although its antiparasitic effects are well documented, the precise molecular targets of Cnd have not been fully defined. The aim of this study was to perform a structure‑based molecular modeling analysis to investigate the direct interaction between candimine and key proteins essential for the survival of <i>T. cruzi</i>. The molecular docking and dynamics simulations revealed favorable interactions between Cnd and <i>T. cruzi</i> squalene synthetase (TcSQS), consistent with previously reported in vitro findings. Docking and simulation analyses showed that Cnd interacts favorably with this target, supporting a mechanism consistent with previous in vitro trypanocide activities. This is the first report to explore potential molecular mechanisms of action, offering new insights into TcSQS as a plausible target and positioning Cnd as a promising natural scaffold for developing next-generation therapies for CD.</p> Graphical abstract <p></p>