Crystallization of Wuchereria Bancrofti Dihydrofolate Reductase in Complex with Methotrexate
Presentation Type
Poster
Faculty Advisor
Nina Goodey
Access Type
Event
Start Date
26-4-2024 2:15 PM
End Date
26-4-2024 3:15 PM
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”, iscaused by the parasitic worm Wuchereria bancrofti. 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. Wuchereria bancrofti DHFR (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. We are also developing a protocol to crystallize Wb DHFR in complex with methotrexate and other inhibitors. This data will be used to understand the interaction between Wb DHFR and methotrexate and other inhibitors and determine how they bind to the “Wb DHFR” active site and what amino acid residues interact with what parts of methotrexate. These data will be useful in designing other compounds that may be potent and selective Wb DHFR inihibitors. The goal of the project is to ultimately repurpose DHFR inhibitors to treat lymphatic filariasis.
Crystallization of Wuchereria Bancrofti Dihydrofolate Reductase in Complex with Methotrexate
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”, iscaused by the parasitic worm Wuchereria bancrofti. 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. Wuchereria bancrofti DHFR (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. We are also developing a protocol to crystallize Wb DHFR in complex with methotrexate and other inhibitors. This data will be used to understand the interaction between Wb DHFR and methotrexate and other inhibitors and determine how they bind to the “Wb DHFR” active site and what amino acid residues interact with what parts of methotrexate. These data will be useful in designing other compounds that may be potent and selective Wb DHFR inihibitors. The goal of the project is to ultimately repurpose DHFR inhibitors to treat lymphatic filariasis.