<p>Cancer cells are distinguished from normal cells by their rapid rate of division. This high division rate can be explained by various factors, including unregulated cell cycle progression, which occurs when cancer cells bypass checkpoints; activation of growth signals in cancer cells; and override of growth suppressor factors, which generally regulate cell growth and division within physiological thresholds. Cancer cells bypass these controls due to genetic mutations or epigenetic changes. Additionally, changes in the tumor microenvironment (TME) can contribute to the accelerated growth and division of cancer cells. It is well established that cancer cells accumulate mutations more frequently than normal cells. This accumulation can, in part, explain their rapid rate of division. The cell cycle consists of four phases: G1, S, G2, and mitosis, with the first three phases categorized as interphase. When cancer cells experience division stress, their demand for nucleotide synthesis increases, which is essential for RNA and DNA synthesis. RNA synthesis primarily occurs during interphase, while DNA replication occurs in the S phase. One of the conserved enzymes involved in nucleotide synthesis is dihydrofolate reductase (DHFR). This enzyme’s role in purine and thymidylate synthesis is crucial in cancerous cells under conditions of division stress. Methotrexate, a well-known DHFR inhibitor, has been introduced for the treatment of cancers such as meningeal leukemia, lymphoma, and breast cancer. While effective in alleviating cancer symptoms, methotrexate can cause adverse effects, including hepatotoxicity, pulmonary complications, and renal impairment. Based on these considerations, we applied combinatorial studies, including molecular dynamics simulations alongside quantum mechanics, to design novel DHFR inhibitors for cancer cells using carbohydrate- and amino acid-based scaffolds. Additionally, our studies suggest that the designed inhibitors may exhibit fewer side effects than methotrexate.</p>