Computer-aided unveiling molecular mechanisms of Xylocarpus granatum against colorectal cancer: therapeutic intervention targeting P13K-AKT signaling pathway.

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality globally, with increasing incidence rates, particularly in early-onset cases. Despite advances in treatment, many developing countries face affordability and safety issues, emphasizing the need for more cost-effective, natural, and safer alternatives. While numerous in vitro studies have reported the anticancer efficacy of mangrove plant Xylocarpus granatum, the molecular mechanisms underlying its effects on CRC remain unexplored. Therefore, our study aimed to uncover the potential therapeutic impact of compounds of X. granatum on CRC to gain insight into novel therapeutic interventions through comprehensive bioinformatics and computational analyses. We aimed to investigate the molecular interactions and mechanisms of Xylocarpus granatum in CRC treatment. Using network pharmacology, patient survival, and cancer hallmarks analysis, we identified 2 significant proteins (AKT1 and ESR1) associated with CRC. On the other hand, utilizing ADMET, quantum chemistry, molecular docking, machine learning, and molecular dynamics simulation, we explored deacetylgedunin (CID 3034112) as the most promising compound derived from Xylocarpus granatum. Our findings revealed that deacetylgedunin exhibited strong binding affinities to AKT1, with docking binding affinity -11.1 kcal/mol and MM-GBSA binding free energy -90.04 kcal/mol. Additionally, molecular dynamics analysis confirmed the stability of the AKT1-CID 3034112 complex, while machine learning (ML) estimation suggested potent biological activity (IC: 114.02 nM) against AKT1, reaffirming its therapeutic potential against CRC, particularly through modulation of the PI3K-AKT signaling pathway. Therefore, our study highlights the promising role of Xylocarpus granatum as a novel therapeutic intervention against CRC by modulating the P13K-AKT signaling pathway. However, our study was limited to computer-aided studies only, and therefore, further experimental validation is necessary to establish the therapeutic efficacy of deacetylgedunin from the Xylocarpus granatum plant in clinical settings.