In Silico Discovery of Natural and Synthetic Inhibitors Targeting AKT1 in Prostate Cancer

The serine/threonine kinase AKT1 plays a pivotal role in cancer progression and therapy resistance, particularly in castration-resistant prostate cancer (CRPC). This study employed an integrated in silico approach to identify potential AKT1 catalytic domain inhibitors from a library of 13,000 compounds sourced from Drugbank and the IMPPAT database. Structure-based virtual screening using AutoDock Vina and AutoDock 4.2 identified five promising candidates, among which 4-Carboxy imidazole and Balanol Analog 2 showed the most favourable binding interactions. Molecular dynamics (MD) simulations revealed that both compounds exhibited low RMSD and RMSF values, indicating stable binding throughout the simulation period. Notably, 4-Carboxy imidazole maintained persistent hydrogen bonding and low solvent exposure, suggesting a compact binding mode. Principal component analysis (PCA) and free energy landscape analyses further supported the conformational stability of these complexes. ADME profiling showed that 4-Carboxy imidazole had superior drug-like properties, while Balanol Analog 2 raised potential concerns related to metabolism. Density Functional Theory (DFT) calculations highlighted favourable electronic properties for both top ligands, with 4-Carboxy imidazole exhibiting a low dipole moment and moderate reactivity, suggesting specificity and stability. While the results are promising, further experimental validation is required to confirm inhibitory activity and therapeutic potential. Overall, this study identifies 4-Carboxy imidazole and Balanol Analog 2 as promising lead compounds for the development of AKT1-targeted therapies in CRPC.