Structural Insights and Drug Repurposing of FDA-Approved Molecules against Human Agmatinase in Cancer Therapy

Background: Cancer remains a significant global health challenge, with ongoing research focused on identifying effective therapeutic targets. Human agmatinase (AGMAT), a binuclear manganese enzyme, has been associated with cancer progression through its role in polyamine production and its involvement in the NO/MAPK/PI3K signaling pathway in lung tissue. Objective: This study aimed to identify potential inhibitors of AGMAT from a library of FDA-approved drugs using computational methods, intending to find novel therapeutic agents for cancer treatment. Methods: The three-dimensional structure of AGMAT was determined using homology modeling, with Pseudomonas guanidinobutyrase (GbuA) serving as the template due to its 74% sequence similarity to AGMAT. The model was validated using PROCHECK, Verify3D, ProSA and ERRAT software. High-throughput virtual screening was conducted on a chemical library of approximately 7922 FDA-approved drugs to identify potential AGMAT inhibitors. Molecular docking simulations assessed the binding affinities of these drugs. Results: The virtual screening identified ten lead FDA-approved molecules: Nemifitidum, Examorelin, Pralmorelin hydrochloride, Nonathymulin, Ebiratide, Lypressin, Histrelin, Agripressin, Cetrorelix and Ornipressin that exhibited significant binding affinities to AGMAT. Conclusion: The identified lead compounds represent promising candidates for further investigation as potential cancer therapeutics targeting AGMAT. These findings provide a basis for future experimental validation and the development of new drugs toward cancer treatments.