Conventional Molecular Dynamics Simulations of the HsDHODH-Lapachol Complex

Dihydroorotate Dehydrogenase (DHODH) is a flavoenzyme essential in the pyrimidine biosynthesis pathway, facilitating the conversion of dihydroorotate to orotate. By catalyzing the fourth step of de novo pyrimidine synthesis, DHODH is crucial for producing UTP (uridine triphosphate) and other pyrimidine nucleotides, which are vital for DNA and RNA synthesis. This enzymatic process directly influences cell proliferation and maintains genomic integrity. Given its pivotal role in pyrimidine production, DHODH serves as a key therapeutic target for treating various diseases. To elucidate the molecular basis of the interaction between Lapachol and human Dihydroorotate Dehydrogenase (HsDHODH), we conducted conventional molecular dynamics simulations using the crystallographic structure of the HsDHODH-Lapachol complex (PDB ID: 9EG9). Three independent simulations, each lasting 1 microsecond, were performed. The results demonstrated that Lapachol remains stable within the binding site throughout the simulations. Key amino acid residues involved in hydrogen bonding with Lapachol include Arg136, Gln47, and His56. Additionally, water-mediated hydrogen bonds were observed between Lapachol and residues Leu359 and Tyr38. These findings suggest that Lapachol maintains its stability at the binding site not only through direct interactions with specific residues but also via indirect interactions, which likely contribute to its overall binding affinity.