Abstract 63P
Background
Molecular similarity assesses similarity between small molecules to discover novel drugs based on available information of target protein and their inhibitors. The PI3Kα/Akt signaling pathway plays a crucial role in cancer development. Mutations in the PIK3CA gene, which encodes the p110α subunit of phosphatidylinositol 3-kinase (PI3K), is found in over breast (>30%), endometrial (>30%), bladder (>20%), colorectal carcinoma (>17%), and head and neck squamous cell carcinoma (>15%) which make it important target. FDA has approved Alpelisib for treating HR+/HER2- breast cancer with PI3Kα mutations in combination with other drugs.
Methods
In this study, we have identified 1,460 molecules with at least 40% structural similarity to Alpelisib by using Tanimoto similarity coefficient. Molecular docking was performed targeting critical residues (Q859 and S854) in the PI3Kα protein to identify promising inhibitors. The molecular dynamics (MD) simulations of lead molecules were performed on GROMACS. The efficacy of identified lead drugs were confirmed using MTT assay and biochemical assays.
Results
The docking results which shows interactions with PI3Kα specificity residues (Q859) were analysed and found two ligands showed the specificity interactions. Further, molecular dynamics simulations results like RMSD, RMSF, SASA, and PCA, confirmed the stability of these complexes over 200 ns of docked lead drug candidate that are Lig I and II. The bonded and non-bonded interactions results like H-bonds, interactions energies, MMPBMSA, and FEL confirmed the interactions. The efficacy of Alpelisib and the selected ligands (Lig I and Lig II) was evaluated using the PI3Kα -wild type (WT) cancer cell lines (MDAMB231 and BT549) and PIK3CA mutant cell lines (MCF7 and T47D). Expression of AKT and phospho-AKT were checked by Western blotting. Interestingly, we found that our identified drug candidate reduced the expression of phospho-AKT.
Conclusions
The drug similarity analysis followed by molecular docking and MD simulation provides leads molecules and the efficacy was conferred my in-vitro studies and two molecules as a potent inhibitor of PI3Kα. Our results indicate that the identified molecules may be potential inhibitors of mutated PI3Kα.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Indian Institute of Technology Bombay, Mumbai, India.
Funding
Indian Institute of Technology Bombay India.
Disclosure
All authors have declared no conflicts of interest.