A computational journey in anticancer drug discovery: Exploring AKT1 inhibition by novel oxadiazoles using molecular docking, ADMET, density functional theory and molecular dynamic simulation.

AKT, also called (PKB) Protein Kinase B, is critical for cell proliferation, metabolism, and survival, with its dysfunction linked to various diseases, including cancer. The oxadiazole nucleus has demonstrated significant anticancer activity in literature surveys. The motivation for conducting this study stems from the fact that, despite numerous investigations into novel therapeutic targets and lead compounds, the inhibition of AKT1 presents limited treatment options due to various adverse drug reactions and specificity issues, given that AKT1 exists in three isoforms. So, this study aimed to identify top-hit molecules with 1,3,4 oxadiazole scaffold targeting the AKT1 enzyme by ligand-based virtual screening to produce a dataset library from PubChem database, structure-based virtual screening followed by ADMET profiling, DFT, and molecular dynamic simulation study as an innovative approach, as there is a dearth of AKT1 inhibitors that comprise oxadiazole in the market and clinical trials. The study employs a combination of advanced computational methods, including virtual screening, molecular docking, molecular dynamics simulations, density functional theory calculations, and ADMET predictions. This comprehensive approach offers a thorough investigation of prospective drug candidates. A comprehensive pharmacoinformatic analysis was conducted on a library of compounds containing oxadiazole rings. A total of 1000 compounds were analyzed through virtual screening utilizing molecular docking and subsequent validation, aiming to identify inhibitors that exhibit a strong affinity for binding for AKT1 (PDB ID: 3O96). Thus, 24 compounds demonstrating binding affinities analogous to the standard emerged as the most promising medicinal prospects and underwent ADMET profiling, and DFT studies followed by a molecular dynamic study on the best 2 compounds. Moreover, these compounds found by ADMET profiling showed suitable pharmacokinetic and pharmacodynamic profiles and were non-toxic using DFT analysis determining ideal structural characteristics. Especially showing comparable stability to the reference molecule over 200 ns in MD simulations, the best top 2 hit compounds having binding affinity -10.7 kcal/mol for PCOS_ 133 (CID-164189) and -11.6 kcal/mol for PCOS3_42 (CID-158973) emerged as potential AKT1 inhibitors for cancer therapy in comparison to -11.6 kcal/mol and -14.7 kcal/mol binding affinity of Miransertib reference drug and IQO cocrystallized ligand of AKT1 protein PDB code 3O96. LEU-210, LEU-264, ASP-292, and TRP-80 are the important amino acid residues required for AKT1 inhibition. These results provide important new perspectives for the rational design and optimization of oxadiazole-based AKT1/PKB inhibitors, therefore laying a strong basis for experimental validation including further in-vitro and in vivo studies and PKB inhibitor development.