198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

44 J.P. Glusker
bonding capabilities of the two compounds are different. Methotrexate is found
in a cavity 15 Å deep in the E. coli enzyme complex. The entire inhibitor molecule
is bound by a system of hydrogen bond and hydrophobic interactions. A
similar binding is found for the E. coli and L. casei enzyme complexes.
The enzyme promotes hydride transfer from NADPH to the pterin ring. This
is facilitated by the development of a charge on C6 and by protonation of N5. The
absolute configuration of tetrahydrofolate has been established [89, 90] to be S
at C6, but if dihydrofolate is bound in the same orientation as methotrexate, the
configuration should be R, as shown in Fig. 35. When dihydrofolate (or tetrahydrofolate)
is bound in the enzyme in the same way as methotrexate, the hydrogen
atom that is transferred to NADPH is pointing in the wrong direction. Thus
dihydrofolate and methotrexate must bind to the enzyme with different orientations
as established later by X-ray crystallographic studies. Studies of additional
bound substrate analogues and inhibitors [91, 92] confirm that binding in
the active site of the enzyme is governed mainly by hydrogen bonding, and not
simply by molecular shape. These situations are illustrated in Fig. 36. They show
that substrate and inhibitor have different and unique binding preferences and
therefore the fact that their modes of binding are different could have been
predicted from our understanding of donor and acceptor roles in hydrogen
bonding (see also the article by A. Naugia and G.R. Desiraju in this volume).
9.2
Binding of Drugs to Nucleic Acids
Antitumor agents that interact with DNA do so in one of three ways.
1. Intercalation between the nucleic acid bases of DNA. This mode of binding is
found for anthracyclines, actinomycin D and acridines. The DNA backbone
flexes so that the bases, normally separated by 3.4 Å, are moved to approximately
7 Å apart. As a result, a flat aromatic molecule can slip between them.
a
Fig. 36 a – c. Binding in dihydrofolate reductase [88]: a binding of the pterin ring of methotrexate
in crystals of the Lactobacillus casei enzyme