netLibrary - eBook Summary Structure-based Drug Design by ...

Document
active site of HIV PR. The inhibitor consists of the central diamino alcohol moiety with symmetrically
distributed phenylalanine side chains and two flanking, Cbz-blocked, valine residues. Except for the
asymmetric hydroxyl group, A74704 binds to the active site in a symmetric mode and the inconsistent
distribution of the terminal Cbz groups is most likely caused by crystal lattice contacts and may not
reflect the binding mode in solution [28].
Page 14
The design of symmetrical inhibitors was further extended to include a series of diamino, diol core units,
in which the C2 axis bisects the bond connecting the two hydroxy-bearing carbon atoms [29]. Such
inhibitors consistently showed greater potency than A74704, but the relative potencies of the diols
differed for different diastereomers, and they did not exhibit a uniform dependence on the
stereochemistry at the hydroxymethyl position. Surprisingly, high-resolution crystal structures of HIV
PR with all possible diol diastereomers, (S,S, R,R and R,S) revealed that most of the inhibitors bind in a
clearly asymmetric fashion placing only one of the diol hydroxyl groups on the C2 axis dissecting the
active site of HIV PR and the catalytic carboxylates of Asp25/25'. The asymmetric placement of diols
causes translation of inhibitors along the long axis of the active site and, as a result, the midpoint of the
compounds is displaced by up to 0.9 Å from the two-fold axis of the HIV PR. Nevertheless, the dihedral
angles of the symmetry-related bonds are in most cases within 10°, and the inhibitors maintain overall
symmetry in the bound conformation [23,29].
The ABT-538 design was a direct consequence of the pioneering work with peptidomimetic compounds
with the internal C2 symmetry [30]. Since the high-resolution crystal structures of a family of diolcontaining
compounds indicated that in most cases only one of the diol hydroxyls interacts with the
catalytic aspartic acids 25/25', in subsequent designs the noninteracting hydroxyl group was replaced by
a hydrogen. This substitution reduced the free energy penalty required for desolvation of the hydroxyl
group and increased the inhibitory potency without perturbing the binding mode of the compounds [30].
In the further search for related inhibitors with improved oral bioavailability, the focus of effort
concentrated on the effect that molecular size, aqueous solubility, and hydrogen-bonding capability has
on pharmacokinetic behavior. This study resulted in a smaller compound, A-80987, in which the P2'
side chain of valine was eliminated and the terminal 2-pyridinyl group was replaced by 3-pyridinyl
moiety that makes van der Waals contacts in the S2' subsite and forms a hydrogen bond with the amide
nitrogen of Asp30 [31]. The pharmacokinetic properties of A-80987 were significantly improved over
larger, symmetrical compounds from this series and, at the same time, the high antiviral activity typical
for these inhibitors was largely unaffected. In subsequent optimization, which focused on the metabolic
stability of these inhibitors in vivo, the electron-rich and oxidation-prone pyridinyl groups were replaced
by thiazoles.
http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_14.html [4/5/2004 4:44:17 PM]