Identificação de compostos de origem vegetal com potencial farmacológico sobre as proteínas PI3Kα e mTOR

Abstract

The PI3K/AKT/mTOR pathway is directly involved in the regulation of major cellular metabolic pathways in mammals. Alterations in this pathway are related to cell survival in several types of cancer, and PI3Kα is the second most mutated oncogenic protein. Overactivation of PI3Kα generates a secondary signaling cascade that stimulates, among others, the activity of mTOR complexes 1 and 2. Given their importance in cancer pathophysiology, the administration of individual or dual inhibitors of PI3Kα and mTOR proteins has been widely explored. However, recent work describes the incidence of side effects as well as pharmacological resistance and highlights the need for the development of new compounds with fewer side effects. In this context, current research targets compounds of plant origin, since this class is known to exhibit antioxidant and anticancer activities. In the present work, computational biology tools were used to identify novel plant-based compounds with selective or dual inhibitory potential on PI3Kα and mTOR enzymes. Initially, computational analyses were performed at the interaction interface between mTOR and mLST8 and the ATP-binding site of mTOR and PI3Kα using interaction energy calculations. Next, conformational sets of mTOR and PI3Kα were obtained by analyzing the anchoring efficiency of the available crystallographic structures for each protein. After validation of the molecular docking strategies, the virtual screening technique based on multi-conformational docking was used to identify plant-derived compounds with dual selective interaction potential with the studied proteins. In total, 1,745 compounds of Brazilian plant origin were tested. Among these, compounds Amentoflavone 7''.4''', Heveaflavone, Podocarpusflavone A, and Amentoflavone were selected and had their binding to the catalytic sites of both proteins investigated. The results indicate that these compounds belong to the class of bioflavonoids, among which, Podocarpusflavone A showed a stereospecific profile for PI3Kα and mTOR. Amentoflavone 7'',4''' showed a racemic profile in binding to PI3Kα while mTOR showed a stereospecific profile. Amentoflavone, on the other hand, showed a specific configuration for PI3Kα and mTOR racemic profile, and Heveaflavone showed a racemic binding profile on both mTOR and PI3Kα. Altogether, the data obtained in this work highlight the role of key residues in PI3K/mTOR inhibition and indicate compounds of plant origin with dual inhibitory potential. These results, besides deepening the knowledge about the inhibition mechanisms of the enzymes studied, also indicate new possibilities for the development of new cancer drugs.