Molecular Docking Reveals Pitavastatin and Related Molecules Antagonize 1DHF and Its Pseudogene DHFR2 in Cancer Treatment

One of the ways in which cancer may develop is via the folic acid biosynthetic pathway. Disruption of this pathway has a toxic effect on rapidly proliferating cells. The enzyme dihydrofolate reductase (DHFR), referred to, as 1DHF in this paper, is critical for DNA synthesis. This enzyme is highly expressed in cancer cells, making it a potential target for anti-cancer drug development. A positive correlation between cholesterol accumulation and cancer provides insight into further investigation of anti-cancer indication of statin drugs. In this study, drug repurposing, data science and other in silico computational methods have been utilized to find a potential statin antagonist of 1DHF and its functional pseudogene, DHFR2. The resolution of the structure of 1DHF retrieved from RCSB PDB was 2.3 Å. A protein similar to 1DHF was identified using protein BLAST. Furthermore, the structure of the protein, DHFR2 was validated with the help of z-scores, Errat results and Ramachandran plot. Docking of statin drugs with both the proteins were done using PyRx. The drug-protein interactions were identified using Discovery Studio. Among the potential statin drugs chosen, pitavastatin showed the highest binding affinities. The values were -12.7kcal/mol with 1DHF and -10kcal/mol with DHFR2. The important amino acids involved in the non-bonding interactions include THR56, TYR121, ILE7, VAL115, PHE31, PHE34, and LEU22 with 1DHF, and PHE32 and PRO27 with DHFR2. The study provides strong indication that pitavastatin could possibly reduce the risk of cancer development when administered as an anti-cancer drug. This study investigates statin drugs that targeted both 1DHF and DHFR2 in the treatment of cancer and found that pitavastatin demonstrated such effect.