Candimine as a natural scaffold for targeting squalene synthetase in Trypanosoma cruzi: insights from computational studies.

Chagas disease (CD), caused by the kinetoplastid protozoan Trypanosoma cruzi, 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 Hippeastrum escoipense (Amaryllidaceae), has recently emerged as a promising compound with activity against T. cruzi. 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 T. cruzi. The molecular docking and dynamics simulations revealed favorable interactions between Cnd and T. cruzi 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.