Identification of thiazolidin-4-one scaffold-based molecules as PI3Kα inhibitors: Molecular docking, MM/GBSA, IFD, ADMET, water-map analysis, and MD simulations

Phosphatidylinositol 3-kinases (PI3Ks) plays an important role in cell growth and proliferation and their dysregulation can lead to metastasis. Among the various isoforms of PI3K, PI3Kα was found to be involved in the progression of multiple cancer types, resulting in its potential to be used as a target for anticancer treatment. Thiazolidin-4-one moiety is widely known for its anticancer effect. However, its inhibitory activity against the enzyme PI3Kα is unexplored. Therefore, our aim is to study the effect of thiazolidine-4-one scaffold on PI3K, especially PI3Kα, and explore its uses as an anticancer agent. Keeping that in focus, we integrated various in-silico screening approaches to identify a potential thiazolidin-4-one moiety-carrying molecule against PI3Kα. A database containing 17,729 compounds with thiazolidine-4-one scaffold was downloaded from Chemdiv and screened initially by docking techniques. The top 10 hits were selected based on extra precision docking results. Alpelisib, an Food and Drug Administration-approved PI3Kα inhibitor, was chosen as the standard. These 10 hits were further subjected to molecular mechanics generalized born surface area (MMGBSA) analysis, where MMGBSA ΔG was calculated, and the top 5 molecules with satisfactory values in comparison to the value of the standard drug were subjected to induced fit docking (IFD). The top 2 hits of IFD were analysed for their absorption, distribution, metabolism, excretion, toxicity properties, and were subjected to a 100 ns molecular dynamics (MDs) simulation, along with the standard drug. From the results of the MD simulation, further filtering out was done using water map analysis, and the molecule that had the best result among the two was subjected to an MD simulation of 500 ns, along with the standard drug. The best molecule and standard drug simulation results were compared to confirm its efficacy as a PI3Kα inhibitor.