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. 2009 May 5;106(18):7455-60.
doi: 10.1073/pnas.0813029106. Epub 2009 Apr 22.

Docking for Fragment Inhibitors of AmpC Beta-Lactamase

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Free PMC article

Docking for Fragment Inhibitors of AmpC Beta-Lactamase

Denise G Teotico et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 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 2Fo-Fc 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).
Fig. 2.
Fig. 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 (A1 to A7) and on the example side chain (A1) 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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