Therapeutic Potential of Phosphodiesterase Inhibitors in Parasitic Diseases - Phosphodiesterases as Drug Targets - page 505

Fig. 7 Putative Leishmania parasite pocket (L-pocket; Wang et al. 2007 ). (a) Superposition of
LmjPDEB1 ( green ribbons , sticks , and labels ) over PDE4D2 ( cyan ribbons , blue sticks , and
labels ). (b) Surface presentation of the unique L-pocket of LmjPDEB1 ( shaded circle labeled
with L) and the equivalent region in PDE4D (c)

the M-loop around Asn881 constitutes the third side of the pocket (Fig. 7a ). Interest-
ingly, the bottom of the pocket is open to the molecular surface of LmjPDEB1. Thus,
the pocket looks more like an open channel. It has a size capable of accommodating a
five-membered ring and shows mixed hydrophilic and hydrophobic characteristics.
At the entrance to the pocket, the two residues Met874 and Gly886 of LmjPDEB1 are
separated by 7.5 ˚ between their C a atoms and serve as a gate open to the

LmjPDEB1 L-pocket.
In human PDE families, however, the amino acids corresponding to the two
entry residues are sitting so close to each other as to isolate the L-pockets from the
main inhibitor binding sites. For example, Met847 and Leu858 in PDE2A, Phe976
and Leu987 in PDE3B, Met357 and Ser368 in PDE4D2, and Leu401 and Ile412 in
PDE7A all block the entry to the L-pocket. In PDE9A, Phe441 and Ala452 do not
block the path, but Val447 moves over by 3 ˚ into the L-pocket and thus fills it up.
In PDE10A, Met713 and Gly725 are separated by 6.7 ˚ , providing an access route
to the L-pocket, but this is blocked by Tyr693. It is interesting to note that a gating
glycine (Gly886 in LmjPDEB1) exists in four of the five LmjPDE families, but only
in human PDE10, and has the largest positional difference among the active site
residues. Since glycine is unique in that its backbone conformation can freely
assume any angle, this residue must represent a fundamental difference between
most human and Leishmania PDEs. In short, we believe that the L-pocket is useful
for the development of Leishmania -selective inhibitors.

3.3 Challenges

T. brucei, T. cruzi ,and Leishmania are closely related parasites, causing very different
diseases, occupy different environments in the human hosts, and hence the develop-
ment of drugs for each indication involves both common and disease-specific