Background: Genome-scale constraint-based metabolic networks play an important role in the simulation of growth coupling, which means that cell growth and target metabolite production are simultaneously achieved. To achieve growth coupling, a minimal reaction-network-based design is known to be effective. However, the obtained reaction networks often fail to be realized by gene deletions due to conflicts with gene-protein-reaction relations.Results: Here, we developed gDel_minRN that determines gene deletion strategies using mixed-integer linear programming to achieve growth coupling by repressing the maximum number of reactions via gene-protein-reaction relations. Computational experiments were conducted in which gDel_minRN was applied to iML1515, a genome-scale model of Escherichia coli. The target metabolites were three vitamins that are highly valuable and require cost-effective bioprocesses for economics and the environment. gDel_minRN successfully calculated gene deletion strategies that achieve growth coupling for the production of biotin (vitamin B7), riboflavin (vitamin B2), and pantothenate (vitaminB5).Conclusion: Since gDel_minRN calculates a constraint-based model of the minimum number of gene-associated reactions without conflict with gene-protein-reaction relations, it helps biological analysis of the core parts essential for growth coupling for each target metabolite. The source codes are implemented in MATLAB, CPLEX, and COBRA Toolbox. The obtained data and source codes are available on https://github.com/taketam/gDel-minRN