In Silico Identification of Chiral Biflavonoids as Dual PI3Kα/mTOR Inhibitors

The PI3K/AKT/mTOR pathway is crucial in regulating key processes in mammalian cells, and impairments of this pathway are associated with cell survival in several cancer types. PI3Kα is the second most mutated oncogenic protein, and its overactivation initiates a secondary signaling cascade that enhances, among others, the activity of mTOR complexes 1 and 2. Despite the importance of this pathway, there is a gap in identifying dual inhibitors targeting both PI3Kα and mTOR, which could potentially overcome the limitations of single-target therapies. In this study, advanced computational tools were employed to identify plant-derived compounds with selective or dual inhibitory potentials against PI3Kα and mTOR enzymes. Compounds were obtained from the NuBBe database, a catalogue of Brazilian natural compounds. Among the 1745 compounds docked against the PI3Kα and mTOR enzymes, four bioflavonoids (2–5) displaying atropisomerism stood out. These compounds were further investigated for their binding profile into the catalytic sites of PI3Kα and mTOR, considering the influence of their sense of chirality (Ra and Sa enantiomers). The results indicate that compound 2 had no enantiopreference for PI3Kα, while (Sa)-2 preferentially bound to mTOR. Compound 3 bound to mTOR in both configurations, while only (Ra)-3 bound to PI3Kα. Compound 4 showed no enantiomeric preference for either protein, whereas compounds (Ra)-5 bound to PI3Kα and (Sa)-5 bound to mTOR. Altogether, these findings highlight the potential of four novel bioflavonoid compounds exhibiting a sense of chirality as promising candidates for the rational design of new cancer therapeutics targeting PI3Kα and mTOR. These insights provide a robust foundation for developing potent dual inhibitors, offering new avenues for treating diseases associated with the hyperactivation of these enzymes. Furthermore, this research underscores the value of plant-derived natural products in developing effective therapeutic agents, contributing significantly to the field of medicinal plant research and advancing the frontier of medicinal chemistry.