NMR K_d, biochemical IC₅₀, and SPR K_d for fragments exploring nucleotide binding pharmacophores.

<p>NMR K_d, biochemical IC₅₀, and SPR K_d for fragments exploring nucleotide binding pharmacophores.</p

Subset of MTH1 substrates with K_m values from experiment and as reported in the literature.

<p>Subset of MTH1 substrates with K_m values from experiment and as reported in the literature.</p

Data collection and structure refinement statistics for MTH1 complexes.

<p><b>Numbers in brackets indicate statistics for the highest resolution shells</b>.</p

Binding modes of 8-oxo-dGTP (yellow carbons) and 3 (cyan carbons).

<p>The water shown is present in the 8-oxo-dGTP structure (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0151154#pone.0151154.g003" target="_blank">Fig 3b</a>) but is displaced in the fragment structure.</p

Binding modes observed in published structures of MTH1 with I): product 8-oxo-dGMP [6] (PDB 3ZR0) and inhibitors II) aminopyrimidine (S)-crizotinib [8] (PDB 4C9X) III) bis-aminopyrimidine TH588 [7] (PDB 4N1U), and IV) an organometal methylaminopyrimidine inhibitor [26] (PDB 3WHW).

<p>The spatial contact motif is summarised in a textual annotation using ‘D’ (donor), ‘A’ (acceptor), ‘C’ (carbon, lipophilic) and ‘-‘ (no near contact) describing the space between protein and ligand. Anchoring motif Asp120-Asp119 is shown for reference.</p

Binding modes of a) 8-oxo-dGTP and b) 8-oxo-rATP c) binding mode fragment 3 d) rotated view of a,b,c from left hand side.

<p>Arrows indicate suggested donor-to-acceptor hydrogen bond directions and dotted lines, interaction of acetate.</p

Key binding and recognition residues of MTH1.

<p>a) Binding site and b) schematic overview. The Asp-Asp motif, Met81, Trp117, Phe27 and Asn33 as well as the water play key roles in recognising and binding the nucleobase. Thr8 interacts with the ribose.</p

Fragment binding modes.

<p>a) binding modes of compounds 5, 6 and 7; b) movement of Asn33.</p

Representation of the chemical diversity of our multi-component reaction aromatic-biased libraries (different chemotypes shown in different colors) relative to the ZINC database [<b>20</b>] (red dots) and four predicted ligands.

<p>The diversity space is visualized by plotting the top two principal components of the OpenBabel FP2 (<a href="http://openbabel.org" target="_blank">http://openbabel.org</a>) fingerprints of 200,000 compounds randomly selected from the 17.5-and-16 million compounds of ZINC and our aromatic-biased database, respectively. The PPI-biased compounds are focused on a different region of chemical space than the historically-biased ZINC database. Indeed, a library of kinase inhibitors, some containing a tryptophan analog, falls squarely in the space covered by ZINC, while inhibitors of p53/MDM2, including inhibitors without a tryptophan analog, are located in the space covered by the new libraries. Four novel compounds from four distinct scaffolds are found to match anchors on the GP41 dimer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032839#pone.0032839-Zwick1" target="_blank">[38]</a>, IKK <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032839#pone.0032839-Hacker1" target="_blank">[39]</a>, IL-2 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032839#pone.0032839-Wang1" target="_blank">[40]</a> and EphB2 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032839#pone.0032839-Pasquale1" target="_blank">[41]</a> receptors. Complete reaction chemistries of the <i>AnchorQuery</i> libraries can be found at <a href="http://anchorquery.ccbb.pitt.edu" target="_blank">http://anchorquery.ccbb.pitt.edu</a>.</p

Two crystal structures of p53/MDM2 inhibitors validate the anchor-centric approach and docked models.

<p>In both structures the indole anchor analog of tryptophan overlaps almost perfectly with W23 in p53 (shown in yellow sticks), when the receptors are aligned the MDM2 structure in the co-crystal (PDB 1YCR). (a) The ligand (purple sticks) of PDB 3LBK has a very similar binding mode to the number one hit in our virtual screen (orange sticks). (b) The crystal pose of the <i>AnchorQuery</i> derived compound (purple) with the predicted pose (green) also aligned very well. The presence of a second ligand near the binding interface distorts the receptor shape relative to the receptor used for docking.</p