\subsection*{Protein Kinase A}

Virtual screening results for protein kinase A (PKA) are shown in Figure~\ref{pka}. For this kinase FOMS substantially outperforms both RDKit (AUC 0.64) and VAMS (AUC 0.55) with an AUC of 0.90.  Shape constraints can perform even better than the full similarity search.  Much of this performance is due to the use of a more selective fragment that properly orients the nitrogen in the ring fragment.  Figure~\ref{pka5} shows the result when a more generic fragment, an arbitrary aromatic ring (PKA$_\mathrm{alt}$ in Table~\ref{fragtable}), is used. The enhanced performance of FOMS disappears, and the ability of shape constraints to generated enriched subsets is reduced. In comparison, the optimizing shape similarity of RDKit performs about the same (AUC 0.62). The use of this fragment pulls in thousands more decoys and introduces many more valid fragment alignments for both actives and decoys.  This implies that the good performance of FOMS and shape constraints with this target is likely due the ability of the fragment to properly position compounds to make conserved interactions with the hinge region of the kinase, as shown in Figure~\ref{targets}.  Compounds that contain the specified fragment but cannot position the fragment to make these interactions while maintaining the steric compatibility of the whole ligand with the query ligand and receptor are filtered out.

%    The best SMARTS expression and approach for PKA performed significantly better than random performance for both FOMS and VAMS (cite stats table). The FOMS approach was significantly better than the VAMS approach for PKA (cite stats table).
%Like many other targets in this dataset, PKA inhibitors interact with the ATP binding site. These inhibitors are relatively smaller in size compared to other inhibitors and have few electrostatic interactions. In the example of 1Q8U and its inhibitor, there is only one hydrogen bond with Val123, where the rest of the ligand makes multiple Van der Waals contacts with other parts of the target (cite PKA). SMARTS expressions and fragment pre-alignment covers the only electrostatic interaction and most of the hydrophobic interactions involved in PKA inhibitors, which most likely led to the high performance of FOMS (cite table).
%More specific SMARTS expressions led to higher performance for FOMS (cite table). This makes sense as the more specific fragment choice would cover the only necessary hydrogen-bond interaction with the receptor. Less specific SMARTS expressions led to higher performance for the VAMS method (cite table). (explanation for why this is).
