On The Cover

The geometry of methotrexate (MTX) in the cocrystal with thymidine synthetase (top) and with dihydrofolate reductase (bottom) is shown in green using atomic coordinates obtained from The Protein Data Bank. Molecular modeling was then used to determine the energy minimized geometry for MTX in these complexes and is shown for each enzyme: MTX complex in yellow. The introduction of a fluorine atom at the 3'-position on MTX (in FMTX) causes only small changes in the geometry of the antifolate within the complexes (shown in red). Slightly more favorable binding energies for FMTX are also predicted based on the molecular modeling results. FMTX is intended to be used as an in vivo ¹⁹F magnetic resonance probe of MTX pharmacokinetics in solid tumors. For details, see 933 in this issue.