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PDBsum entry 3gr2
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Hydrolase/hydrolase inhibitor
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PDB id
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3gr2
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References listed in PDB file
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Key reference
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Title
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Docking for fragment inhibitors of ampc beta-Lactamase.
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Authors
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D.G.Teotico,
K.Babaoglu,
G.J.Rocklin,
R.S.Ferreira,
A.M.Giannetti,
B.K.Shoichet.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
7455-7460.
[DOI no: ]
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PubMed id
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Abstract
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Fragment screens for new ligands have had wide success, notwithstanding their
constraint to libraries of 1,000-10,000 molecules. Larger libraries would be
addressable were molecular docking reliable for fragment screens, but this has
not been widely accepted. To investigate docking's ability to prioritize
fragments, a library of >137,000 such molecules were docked against the
structure of beta-lactamase. Forty-eight fragments highly ranked by docking were
acquired and tested; 23 had K(i) values ranging from 0.7 to 9.2 mM. X-ray
crystal structures of the enzyme-bound complexes were determined for 8 of the
fragments. For 4, the correspondence between the predicted and experimental
structures was high (RMSD between 1.2 and 1.4 A), whereas for another 2, the
fidelity was lower but retained most key interactions (RMSD 2.4-2.6 A). Two of
the 8 fragments adopted very different poses in the active site owing to enzyme
conformational changes. The 48% hit rate of the fragment docking compares very
favorably with "lead-like" docking and high-throughput screening against the
same enzyme. To understand this, we investigated the occurrence of the fragment
scaffolds among larger, lead-like molecules. Approximately 1% of commercially
available fragments contain these inhibitors whereas only 10(-7)% of lead-like
molecules do. This suggests that many more chemotypes and combinations of
chemotypes are present among fragments than are available among lead-like
molecules, contributing to the higher hit rates. The ability of docking to
prioritize these fragments suggests that the technique can be used to exploit
the better chemotype coverage that exists at the fragment level.
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Figure 1.
Overlay of docked pose (green) and crystallographic pose
(orange) for 8 of the fragment inhibitors prioritized by
docking. The compounds shown are: 8 (A), 20 (B), 21 (C), 1 (D),
12 (E), 22 (F), 3 (G), and 5 (H). The final 2F[o]-F[c] maps
contoured at 1σ are shown for A–E, G, and H. Compound 22,
although discovered as part of the docking screen described
here, was reported previously and no density is shown for it
(24).
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Figure 2.
Illustration of fragment substructures and their expansions
with side chains. (A) The fragment (red, Left) is a substructure
of the larger lead-like compound (Right). (B) The number of
attachment points on the fragment scaffold (A[1] to A[7]) and on
the example side chain (A[1]) was determined by generating
smiles strings of each and identifying the number of hydrogen
atoms. Each decoration was allowed only 1 attachment point at a
time (excluding ring closing within the fragment). The possible
number of lead-like expansions (≤25 HAC) that could be formed
by combining each decoration to attachment points on the 23
fragment scaffolds was calculated analytically by using Eq. 3.
(C) Structures of the different kinds of symmetry elements seen
in the fragments. In each case, the symmetrical attachment
points (e.g., A1 and A2, C1, C2, and C3) were collapsed into a
single attachment point (e.g., A1 and A2 count as only 1
attachment point). These provided a lower limit for the possible
number of compounds that contain the fragments as substructures.
The upper limit is calculated by assuming each attachment point
is unique (no symmetry).
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