Molecular Pharmacology, Vol 13, 1111-1115, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Calculations by Complete Neglect of Differential Overlap (CNDO/2) on Dihydrofolic Acid: Role of N(5) in Reduction by Dihydrofolate Reductase

¹ Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065

CNDO/2 calculations on 7,8-dihydropteroylamide, a model of 7,8-dihydrofolic acid, have been 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/mole. This first site of protonation and the conformational preference agree with those observed in solution for 7,8-dihydrofolic acid. The lowest unoccupied molecular orbital (LUMO) of the N(5)-cation exhibited a much higher wave function magnitude at C(6) than did the LUMO of the N(1)-cation or the neutral molecule. Thus, 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 ultraviolet difference spectra of dihydrofolate reductase upon binding of dihydrofolate, indicative of protonation of dihydrofolate at N(5) upon binding. The protonation-upon-binding argument also may explain why dihydrofolate is so potently inhibited by analogues more basic than dihydrofolate in its pteridinyl moiety.

Note:
ACKNOWLEDGMENT Len Olen assisted with the calculations.

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