Dihydrofolate reductase inhibitors Flashcards
Examples of DHFR-I
Pyrimethamine = anti malarial Trimethoprim = antibacterial Methotrexate = anti cancer / anti arthritic
MoA of DHFR-inhibitors
Folate antagonists
Inhibits the processing of folic acid
Competitively inhibits the bacterial enzyme dihydrofolate reductase required for the conversion of dihydrofolic acid to tetrahydrofolic acid
Inhibiting DHFR = inhibits synthesis of thymidine and DNA synthesis
Why is DHFR a good target?
There is significant structural variation of DHFR between species (man and bacteria) = selective to bacterial cells = reduced s/e
Structural differences = size, shapes and charge distribution of enzyme active site
The only source of thymidine required for DNA synthesis is the folate mediated addition of methyl group to dUMP = inhibit the mechanism inhibits thymidine synthesis
Bacteria needs large amount of nucleic acid to replicate = reduction in thymidine = can’t replicate
How can you reduce toxicity of DHFR methotrexate?
Leucovorin recovers the damage caused by methotrexate as it is metabolised to methylene tetrahydrofolate therefore there’s no need for the tetrahydrofolate produces by DHFR to synthesise thymidine
How is thymidine monophosphate synthesised?
Dihydrofolate reductase reduces dihydrofolate to tetrahydrofolate
Thimydylate synthase takes a methyl group from tetrahydrofolate and places it on dUMP leading to the synthesis of dTMP
Why is thymidine monophosphate important?
It is an essential nucleotide for DNA synthesis