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Figure 5.
Figure 5. Model of the transition-state analog bound to
CNJ206. (a) The same view as in Figure 2, illustrating a model
of p-nitrophenyl methylphosphonate (compound 3 of Figure 1)
bound to CNJ206. The inhibitor 3 was modeled using SYBYL
(Molecular Modeling Software, Tripos Associates, St Louis, MO)
and structural data [43] and adjusted into the binding site of
CNJ206 using FRODO [44]. Atomic positions were then subjected to
energy refinement with X-PLOR [41]. Atoms further than 9
å from the hapten were kept fixed, while soft harmonic
constraints were applied to atoms in a shell between 7 and 9
å from the hapten. For residues within 7 å of the
hapten, softer constraints were applied to main-chain atoms,
while side chains were left unconstrained. Polar or charged
residues lining the cavity are labeled. The intramolecular salt
link between Arg L46 and Asp L55, which stabilizes the
conformation of the arginine is shown. The orientation
presented allows hydrogen bonds (dotted lines) to be made both
to the nitro group and to the methyl phosphonate (atom colours
as described for Figure 4). (b)A space-filling representation
of the same model. The phosphorous atom is shown here in green
with the phenyl ring and methyl group of compound 3 in yellow.
In this orientation, compound 3 buries 242 å ^2of
surface, which is 71 % of its total accessible surface area
(calculated using a 1.4 å radius probe). Figure 5.
Model of the transition-state analog bound to CNJ206. (a) The
same view as in [3]Figure 2, illustrating a model of
p-nitrophenyl methylphosphonate (compound 3 of [4]Figure 1)
bound to CNJ206. The inhibitor 3 was modeled using SYBYL
(Molecular Modeling Software, Tripos Associates, St Louis, MO)
and structural data [[5]43] and adjusted into the binding site
of CNJ206 using FRODO [[6]44]. Atomic positions were then
subjected to energy refinement with X-PLOR [[7]41]. Atoms
further than 9 å from the hapten were kept fixed, while
soft harmonic constraints were applied to atoms in a shell
between 7 and 9 å from the hapten. For residues within 7
å of the hapten, softer constraints were applied to
main-chain atoms, while side chains were left unconstrained.
Polar or charged residues lining the cavity are labeled. The
intramolecular salt link between Arg L46 and Asp L55, which
stabilizes the conformation of the arginine is shown. The
orientation presented allows hydrogen bonds (dotted lines) to be
made both to the nitro group and to the methyl phosphonate (atom
colours as described for [8]Figure 4). (b)A space-filling
representation of the same model. The phosphorous atom is shown
here in green with the phenyl ring and methyl group of compound
3 in yellow. In this orientation, compound 3 buries 242 å
^2of surface, which is 71 % of its total accessible surface area
(calculated using a 1.4 å radius probe).
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