Identifying potential inhibitors of phosphatidylinositol 4,5-bisphosphate 3-kinase: Molecular dynamic insights into the interaction and inhibitory mechanism

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) plays a crucial role in signaling pathways and has emerged as an attractive target for anticancer therapy. Developing small-molecule inhibitors targeting PIK3CA has emerged as a promising therapeutic strategy. Here, we employed in-silico approaches to identify potential inhibitors of PIK3CA from a pool of bioactive phytoconstituents available from IMPPAT 2.0 database. The initial screening was based on their drug-like properties and docking score, followed by interaction analysis and 100 nanoseconds (ns) molecular dynamics (MD) simulations to evaluate their conformational stability with PIK3CA. MD simulation studies suggested the formation of stable complexes between PIK3CA and the elucidated compounds Apollinine and Isoglycyrol. These compounds exhibited exceptional drug-like properties, potential binding efficiency, and remarkable stability. The findings suggest that Apollinine and Isoglycyrol could serve as potential leads in the therapeutic development of PIK3CA inhibitors for targeting cancer. Moreover, the insights gained from the simulation dynamics shed light on the molecular mechanisms of PIK3CA inhibition that facilitate the rational design of future inhibitors.