Virtual Screening and Molecular Simulation of Drug Candidates Targeting the Human SLC4A4 Protein for Colorectal Cancer Therapy

Background Colorectal cancer is a highly complex disease that continues to rise in prevalence, posing significant difficulties in its management and treatment outcomes. Reduced expression of the SLC4A4 gene has been identified as a critical factor in driving tumor development and poor clinical prognosis in CRC. This reduction disrupts several key cellular mechanisms, including cellular proliferation, programmed cell death, and metastasis, largely by altering pH regulation within the cells. Given its influence on tumor behavior and patient survival, SLC4A4 expression levels could serve as a reliable prognostic marker in colorectal cancer. Methods The CryoEM structure of SLC4A4, retrieved from the Protein Data Bank (PDB), was refined using SwissModel and subjected to virtual drug screening via the DrugRep web server. This screening employed a database comprising FDA-approved drugs. Results Nilotinib emerged as the most potent inhibitor following further validation through redocking using CB-DOCK2, ranking it highest among the top three results from DrugRep. The docking analysis yielded a score of −11.2 kcal/mol for Nilotinib. A 50-nanosecond molecular dynamics simulation further validated these findings, revealing that Nilotinib formed robust interactions with the SLC4A4 protein. The simulation yielded consistent results, with a root mean square deviation of around 0.30 nm, a root mean square fluctuation of near 0.5 nm, a compact radius of gyration between 3.8 and 4.0 nm, and stable solvent-accessible surface area profiles. These findings confirmed that the drug-protein complex maintained structural stability throughout the simulation. Discussion The computational findings suggest that Nilotinib binds effectively and stably to SLC4A4, indicating its potential to modulate the function of this protein in CRC. Its established safety profile as an FDA-approved drug supports the feasibility of drug repurposing. These results also reinforce the utility of integrating structure-based drug screening with molecular dynamics simulations to identify novel therapeutic agents for cancer. Conclusion Nilotinib holds significant potential as a therapeutic agent for colorectal cancer and warrants further experimental investigation to validate its effectiveness.