Structural analysis of Wuchereria bancrofti dihydrofolate reductase in complex with methotrexate and TSD compounds
Presentation Type
Abstract
Faculty Advisor
Nina Goodey
Access Type
Event
Start Date
25-4-2025 9:00 AM
End Date
25-4-2025 9:59 AM
Description
Over 882 million people in 44 countries are still at risk for lymphatic filariasis and the current form of treatment is preventive chemotherapy. Lymphatic filariasis, a disease commonly known as “elephantiasis”, is caused by the parasitic worm Wuchereria bancrofti (Wb DHFR). We are studying the enzyme dihydrofolate reductase (DHFR) in this parasitic worm. DHFR is an established drug target due to its ability to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) using NADPH as a cofactor. DHFR is currently a drug target in the treatment of cancer and bacterial diseases. Wb DHFR is known to be inhibited by methotrexate but methotrexate also inhibits the human DHFR. Our research goal is to determine if there are other inhibitors that can inhibit Wb DHFR without interfering with the human DHFR. Wb DHFR was successfully crystallized in complex with methotrexate and inhibitors TSD1, TSD10 and TSD 25. These structures revealed how the inhibitors bind to the active site and the type of interactions they form with the active site residues of the enzyme. These data will be useful in identifying other antifolate compounds with similar pharmacophores as methotrexate that may be potent and selective Wb DHFR inhibitors. The goal of this research is to ultimately repurpose DHFR inhibitors to treat lymphatic filariasis.
Structural analysis of Wuchereria bancrofti dihydrofolate reductase in complex with methotrexate and TSD compounds
Over 882 million people in 44 countries are still at risk for lymphatic filariasis and the current form of treatment is preventive chemotherapy. Lymphatic filariasis, a disease commonly known as “elephantiasis”, is caused by the parasitic worm Wuchereria bancrofti (Wb DHFR). We are studying the enzyme dihydrofolate reductase (DHFR) in this parasitic worm. DHFR is an established drug target due to its ability to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) using NADPH as a cofactor. DHFR is currently a drug target in the treatment of cancer and bacterial diseases. Wb DHFR is known to be inhibited by methotrexate but methotrexate also inhibits the human DHFR. Our research goal is to determine if there are other inhibitors that can inhibit Wb DHFR without interfering with the human DHFR. Wb DHFR was successfully crystallized in complex with methotrexate and inhibitors TSD1, TSD10 and TSD 25. These structures revealed how the inhibitors bind to the active site and the type of interactions they form with the active site residues of the enzyme. These data will be useful in identifying other antifolate compounds with similar pharmacophores as methotrexate that may be potent and selective Wb DHFR inhibitors. The goal of this research is to ultimately repurpose DHFR inhibitors to treat lymphatic filariasis.
Comments
Poster presentation at the 2025 Student Research Symposium.