Epi -croomine and croomine from Stemona tuberosa antimalarial drug for inhibiting dihydrofolate reductase (DHFR) activity and their molecular modeling

One of the mechanism actions of antimalarial drugsi s by an inhibiting on the enzyme dihydrofolate redu ctase (DHFR), an enzyme target antifolate drug. Epi-croom ine and croomine , are alkaloids isolated from Stemonatuberosa showed DHFR inhibition with K i of 61.14 and 100.59 µM and K M values of30.68 and 27.06 µM at 10 ppm. The IC 50 to the DHFR of croomine and pyrimethamine were 5.2 9 and 7.71 µM, respectively. Tuberostemonine is not active to the enzyme. The ki netic analysis showed that both epi-croomine and cr oomine competitively inhibited to the human DHFR recombina nt. The molecular modeling of the compounds to the human DHFR was estimate depi-croomine and croomine’s bind ing free energy of -6.66 and -7.60 kcal/mol. The do cking showed that both epi-croomine and croomine could po ssibly form hydrogen bonds with the amino acid resi due of theAla9, which residues on the active site of the e nzyme.