MOLECULAR TARGETS AS POTENTIAL PI3Kα INHIBITORS AGAINST AGGRESSIVE METASTATIC DUCTAL AND LOBULAR CARCINOMA

Abstract

Objective: This study aimed to identify active compounds among existing molecules by drug repositioning as potential hits of Phosphoinositide 3-Kinase (PI3Kα) inhibitors. FDA-approved ligands were docked using structure-based in silico screening, and the top ten molecules based on docking score were studied for their in silico pharmacokinetic and ligand-receptor interactions.

Methods: FDA-approved ligands were docked with the protein PI3Kα enzyme (PDP ID: 4JPS) and were checked for their molecular interactions and docking scores using the GLIDE program of Schrödinger software. The top 10 ligands were subjected to ADMET and MMGBSA studies to predict pharmacokinetic properties and binding affinity. The best two molecules and the standard alpelisib were subjected to Molecular dynamics with 100 nsec simulation time to deduce interaction at the atomic level.

Results: Two molecules, ZINC000003794794 (Mitoxantrone) and ZINC000004098633 (Polydatin), were found to be promising based on docking score, ligand interaction diagram, and MMGBSA scores of-13.084 and-11.364 and-75.38 and-58.88 respectively and were in a comparable range to the standard alpelisib. These two molecules were then subjected to Induced Fit Docking (IFD) and molecular dynamics to better understand protein stability and inhibitor activity in physiological conditions. The IFD values of these molecules were very close to the standard, and the residues of the best poses coincided with the desired residues, such as V851, S854, and Q859, seen in the alpelisib.

Conclusion: However, further in vitro and in vivo screening is needed to confirm the PI3Kα inhibitory activity of these ligands, which could serve as promising lead molecules in treating TNBC with fewer side effects compared to existing drugs.