Open AccessPreferential selection of isomer binding from chiral mixtures: alternate binding modes observed for the E and Z isomers of a series of 5‐substituted 2,4‐diaminofuro[2,3‐ d ]pyrimidines as ternary complexes with NADPH and human dihydrofolate reductase
Author(s) -
Cody Vivian,
Piraino Jennifer,
Pace Jim,
Li Wei,
Gangjee Aleem
Publication year - 2010
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444910035808
Subject(s) - stereochemistry , chemistry , ring (chemistry) , isopropyl , pyrimidine , substituent , medicinal chemistry , organic chemistry
The crystal structures of six human dihydrofolate reductase (hDHFR) ternary complexes with NADPH and a series of mixed E / Z isomers of 5‐substituted 5‐[2‐(2‐methoxyphenyl)‐prop‐1‐en‐1‐yl]furo[2,3‐ d ]pyrimidine‐2,4‐diamines substituted at the C9 position with propyl, isopropyl, cyclopropyl, butyl, isobutyl and sec ‐butyl ( E 2– E 7, Z 3) were determined and the results were compared with the resolved E and Z isomers of the C9‐methyl parent compound. The configuration of all of the inhibitors, save one, was observed as the E isomer, in which the binding of the furopyrimidine ring is flipped such that the 4‐amino group binds in the 4‐oxo site of folate. The Z 3 isomer of the C9‐isopropyl analog has the normal 2,4‐diaminopyrimidine ring binding geometry, with the furo oxygen near Glu30 and the 4‐amino group interacting near the cofactor nicotinamide ring. Electron‐density maps for these structures revealed the binding of only one isomer to hDHFR, despite the fact that chiral mixtures ( E : Z ratios of 2:1, 3:1 and 3:2) of the inhibitors were incubated with hDHFR prior to crystallization. Superposition of the hDHFR complexes with E 2 and Z 3 shows that the 2′‐methoxyphenyl ring of E 2 is perpendicular to that of Z 3. The most potent inhibitor in this series is the isopropyl analog Z 3 and the least potent is the isobutyl analog E 6, consistent with data that show that the Z isomer makes the most favorable interactions with the active‐site residues. The isobutyl moiety of E 6 is observed in two orientations and the resultant steric crowding of the E 6 analog is consistent with its weaker activity. The alternative binding modes observed for the furopyrimidine ring in these E / Z isomers suggest that new templates can be designed to probe these binding regions of the DHFR active site.