Identification of natural product as selective PI3Kα inhibitor against NSCLC: multi-ligand pharmacophore modeling, molecular docking, ADME, DFT, and MD simulations.

Non-small cell lung cancer (NSCLC) is a widespread and often aggressive form of cancer affecting people worldwide. PIK3CA missense mutations play a significant role in the progression of growth factor signaling in cancer, making PI3Kα an important biological target for inhibition against NSCLC. Natural product molecules with PI3Kα inhibitory activity are promising therapeutic agents for the treatment of NSCLC, owing to their selectivity and potentially lower toxicity compared to synthetic compounds. To discover new natural product molecules, we integrated ligand-based virtual screening with structure-based virtual screening. We developed a multi-ligand pharmacophore hypothesis, validated it with 3D Field-based QSAR, and screened a Natural-Product-Based Library (ChemDiv) containing 3601 molecules. After initial screening, 137 hit molecules were generated and further screened using the extra precision (XP) Glide docking protocol. The best ten molecules were selected for free binding energy (ΔG) analysis using MMGBSA and ADME predictions. For further optimization, the top four hits were subjected to induced fit docking (IFD), quantum chemical descriptors analysis by Frontier Molecular Orbital (FMO) studies, and a 100 ns molecular dynamics (MD) simulation. The compounds-S721-1955, CM4579-5085, S721-1963, and S721-1999-exhibited better results than the PI3Kα selective inhibitor alpelisib. In silico prediction analysis of S721-1955 and alpelisib revealed that the former exhibited superior selectivity theoretically, as evidenced by its higher affinity for the target protein. The selective natural product molecule identified in this study holds promise as a potential anti-cancer drug against NSCLC in the near future, but further in vitro and in vivo studies are necessary to confirm its efficacy.