We designed a series of pyrido[2,3-d]pyrimidine derivatives based on the structure of the NEK6 kinase inhibitor, compound 21 (2-amino-5-phenyl-5,11-dihydro-3H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-4,6-dione), which share the same heterocyclic core. Chemical modifications, aimed at altering the molecular planarity of 21 to enhance water solubility, were guided by receptor-based ligand design and further supported by molecular docking, molecular dynamics simulations, and free energy perturbation calculations. Our results indicate that disrupting the planarity of 21 increases aqueous solubility - nearly doubling it in two cases- while reducing lipophilicity. Among the compounds tested, three showed both improved solubility and NEK6 inhibitory activity exceeding 50% in single-dose assay.