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 28,008 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 affinities (−9.553, −9.301 kcal/mol), comparable to the co-crystalised reference ligand XOO (−3.092 kcal/mol). Docking protocol validation through re-docking of XOO yielded an RMSD of 2.950 Å, confirming the reliability of the docking procedure. Molecular dynamics (MD) simulations (300 ns) revealed that both compounds exhibited low RMSD (values ranging from 0.64–5.53 Å), comparable to the reference complex RMSD (values ranging from 0.879–8.136 Å). RMSF analysis indicated limited residue fluctuations within the binding pocket, while hydrogen bond analysis revealed persistent interactions contributing stable binding throughout the simulation period. Principal component analysis (PCA) and free energy landscape (FEL) analyses further supported the conformational stability and restricted motion of ligand-bound AKT1 complexes relative to the reference system. ADME profiling showed that 4-Carboxy imidazole had superior drug-like properties, while Balanol Analog 2 raised potential concerns related to metabolism. Toxicity predictions for both compounds were generally within acceptable limits, with no strong indications of mutagenicity or cytotoxicity. Density Functional Theory (DFT) calculations highlighted favourable electronic properties for both top ligands, 4-Carboxy imidazole and Balanol Analog 2 exhibiting a low dipole moment and moderate HOMO–LUMO energy gaps (4.279 and 3.057 eV respectively), 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.