3K45

Alternate Binding Modes Observed for the E- and Z-isomers of 2,4-Diaminofuro[2,3d]pyrimidines as Ternary Complexes with NADPH and Mouse Dihydrofolate Reductase

Summary for 3K45

• Entry DOI: 10.2210/pdb3k45/pdb
• Related: 3K47
• Descriptor: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-[(1Z)-2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamine, ... (4 entities in total)
• Functional Keywords: protein ligand cofactor ternary complex, nadp, one-carbon metabolism, oxidoreductase
• Biological source: Mus musculus (mouse)
• Cellular location: Mitochondrion : P00375
• Total number of polymer chains: 1
• Total formula weight: 22531.56

Authors

Cody, V. (deposition date: 2009-10-05, release date: 2009-10-13, Last modification date: 2023-09-06)

Primary citation

Gangjee, A.,Li, W.,Lin, L.,Zeng, Y.,Ihnat, M.,Warnke, L.A.,Green, D.W.,Cody, V.,Pace, J.,Queener, S.F.
Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors.
Bioorg.Med.Chem., 17:7324-7336, 2009

PubMed Abstract: To optimize dual receptor tyrosine kinase (RTK) and dihydrofolate reductase (DHFR) inhibition, the E- and Z-isomers of 5-[2-(2-methoxyphenyl)prop-1-en-1-yl]furo[2,3-d]pyrimidine-2,4-diamines (1a and 1b) were separated by HPLC and the X-ray crystal structures (2.0 and 1.4A, respectively) with mouse DHFR and NADPH as well as 1b with human DHFR (1.5A) were determined. The E- and Z-isomers adopt different binding modes when bound to mouse DHFR. A series of 2,4-diaminofuro[2,3-d]pyrimidines 2-13 were designed and synthesized using the X-ray crystal structures of 1a and 1b with DHFR to increase their DHFR inhibitory activity. Wittig reactions of appropriate 2-methoxyphenyl ketones with 2,4-diamino-6-chloromethyl furo[2,3-d]pyrimidine afforded the C8-C9 unsaturated compounds 2-7 and catalytic reduction gave the saturated 8-13. Homologation of the C9-methyl analog maintains DHFR inhibitory activity. In addition, inhibition of EGFR and PDGFR-beta were discovered for saturated C9-homologated analogs 9 and 10 that were absent in the saturated C9-methyl analogs.

PubMed: 19748785
DOI: 10.1016/j.bmc.2009.08.044

Experimental method

X-RAY DIFFRACTION (1.6 Å)