An In Silico Investigation of Novel Oxadiazoles as ATP-Competitive AKT1 Inhibitors for Anticancer Applications through Molecular Docking,ADMET, and DFT Studies

Introduction: AKT1, or protein kinase B (PKB), is required for the survival, growth, and metabolism of cells. Many disorders, including cancer, are linked to its malfunction. Literature reviews indicate that the Oxadiazole nucleus has anticancer activity. Using ligand-based virtual screening in PubChem, this study aimed to identify the most effective 1,3,4-Oxadiazole scaffold compounds that interact with AKT1, followed by molecular docking and ADMET profiling. Methods: We conducted a pharmacoinformatic analysis of the Oxadiazole-ring library identified via ligand-centric computational evaluation, performing virtual screening of 1000 compounds using molecular docking and validation, which led to the identification of AKT1 ATPcompetitive inhibitors with significant binding affinity (PDB ID: 3CQW). The leading candidates underwent rigorous ADMET profiling to assess their pharmacokinetic and pharmacodynamic properties, and DFT analysis to examine the structural determinants of stability and reactivity. Results: Consequently, we selected 12 compounds exhibiting optimal binding affinities as the premier pharmacological candidates for ADMET profiling. We discovered non-toxic compounds with advantageous pharmacokinetic and pharmacodynamic properties, while DFT analyses evaluated and confirmed structural integrity and reactivity. The top hit compound PCOS_133 (CID-164189) demonstrated a binding affinity of -9.9 kcal/mol, outperforming the reference drug Capivacertib (-8.9 kcal/mol) and the co-crystallized ligand CQW (-7.9 kcal/mol) of the AKT1 protein (PDB: 3CQW), highlighting its strong potential as an ATP-competitive AKT1 inhibitor for cancer therapy. Discussion: All 12 hit compounds exhibited higher binding affinities than both reference ligands, further supporting their inhibitory potential. Crucial amino acid residues involved in ATP-competitive inhibition, ALA-230, GLU-234, THR-291, ALA-177, MET-227, VAL-164, and MET-281, were consistently engaged across all 12 hits, reinforcing their relevance in targeted AKT1 binding. Potent molecules selected has shown better binding affinities compared to the 3CQ with binding score with the of these, the leading AKT1 ATP competitive inhibitors, PCOS_133 (CID: 164189122), PCOS3_309 (CID: 155926295), PCOS_572 (CID: 156012047), PCOS_609 (CID: 166197901), and PCOS_573 (CID: 156010927), demonstrated favourable ADMET properties, nontoxic profiles, and high potential as AKT1 ATP competitive inhibitors. Conclusion: This study demonstrates that 1,3,4-Oxadiazole derivatives have therapeutic potential as AKT1 inhibitors. The defined lead compounds are promising candidates for subsequent experimental validation and optimization, thereby facilitating the advancement of targeted anticancer therapeutics.