Investigation of the Dissociation Process of the Inhibitor Methotrexate from the Methotrexate-Lactobacillus Casei Dihydrofolate Reductase Complex by Using Molecular Dynamics and Semiempirical Molecular Orbital Methods

NADPH-dependent dihydrofolate reductase (DHFR) catalyzes the two-stage reduction of folate to the vital coenzyme tetrahydrofolate. DHFR inhibitors such as aminopterin or amethopterin (methotrexate) have demonstrated clinical utility in the treatment of acute leukemia and choriocarcinoma. We employed molecular dynamic simulation techniques and semiempirical calculations to investigate the dissociation process of methotrexate (MTX) from the MTX-DHFR complex of Lactobacillus casei . The simulation enables the researcher to examine time dependent conformational and electronic changes of the MTX-DHFR complex during the dissociation process.