Calculations by complete neglect of differential overlap (CNDO/2) on dihydrofolic acid: role of N (5) in reduction by dihydrofolate reductase
Gund, P.; Poe, M.; Hoogsteen, K.H.
Molecular Pharmacology 13(6): 1111-1115
1977
ISSN/ISBN: 0026-895X PMID: 593265 Document Number: 117875
CNDO/2 calculations on 7,8-dihydropteroylamide, a model of 7,8-dihydrofolic acid, were made to examine the conformational and electronic properties of the molecule. The quantum mechanical calculations indicate that while the extended forms of the neutral molecule, its N(1)-cation and N(5)-cation were favored with respect to folded forms, bent conformations are probably energetically accessible. Calculated binding energies for the protonated cations suggested that protonation at N(5) is strongly favored over N(1) by about 16.4 kcal/mol. This 1st site of protonation and the conformational preference agree with those observed insolution fo ,8-dihydrofolic acid. The lowest unoccupied molecular orbital (LUMO) of the N(5)-catio exhibited a much higher wave function magnitude at C(6) than did the LUMO of the N(1)-cation or the neutral molecule. According to frontier orbital theory, the N(5)-cation is especially well suited for hydride transfer to C(6). This latter result rationalizes the observed UV difference spectra of dihydrofolate reductase [EC 1.5.1.3. an important drug target in human infections and cancer chemotherapy.] on binding of dihydrofolate, indicative of protonation of dihydrofolate at N(5) on binding. The protonation on-binding argument also may explain why dihydrofolate is so potently inhibited by analogs more basic than dihydrofolate in its pteridinyl moiety.