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FOMS dramatically outperformed other methods for the Rho and PKA targets due to correct positioning of a fragment with key, conserved interactions.   FOMS essentially provides a rapid means of template docking \cite{Ruiz_Carmona_2014,abagyan2015icm,Koes_2012} using shape-based scoring. The disadvantage of fragment-oriented approaches is they are critically dependent on the choice of fragment and its proper positioning in defining the query. Provided these requirements can be met, there are several advantages to shape-based fragment alignment search. By enforcing the fragment alignment, key interaction are guaranteed to be conserved. Previous results have demonstrated the importance of adding pharmacophoric properties (or `color') to shape similarity \cite{Hawkins_2007}. Fragment alignment introduces a hard bias toward matching a key portion of the query molecule without introducing any additional computation or calculation, as required by more general methods. In fact, as we have shown, pre-alignment substantially reduces the computational overhead. Prealignment, whether to fragments (FOMS) or canonical internal coordinates (VAMS) is orders of magnitude faster than methods that dynamically optimize the alignment. This holds true even if the cost to create the search database is taken into account. The time to create the databases scales with the number of molecular shapes (about 10 shapes a second on our system) and compares favorable with RDKit search (2 molecules a second).  As the common case is for a fragment oriented database to be re-used to for queries by multiple and users investigating multiple targets, in practice the cost of database creation gets amortized into insignificance.  A major advantage of fragment alignment is that it enables the use of shape constraints.  Shape constraint search generally tracked or improved upon the performance of FOMS similarity ranking (e.g. Figure~\ref{cathg}). As shown in Table~\ref{pvaltable}, shape constraints were able to generate statistically significant ($p < 0.01$) enriched subsets for six of the ten targets.  Unlike whole-molecule shape similarity, shape constraint can select for a \textit{subshape} of the query ligand and specifically filter out potential clashes with the receptor.  The expected use case for these algorithms is for scenarios where a number for fragment-oriented databases are created to enable repeated searches by multiple users investigating multiple targets, in which case the cost of database creation essentially gets amortized into insignificance.  Shape constraints provide a novel and unique method for specifying molecular shape queries. Since they are fragment oriented, they can be used to perform partial shape similarity search, a generaly challenging problem (cite). Shape constraint searches generally took well under a second making them perfect for interactive applications. Although we have investigated automatically generated shape constraints, our assumption is that intelligently designed constraints created by human experts guided by interactive analysis of a virtual screening database would substantially outperform our interaction point based constraints. This hypothesis remains untested as intuitive interfaces that allow expert users to sculpt their desired molecule need to be developed and integrated into a comprehensive virtual screening evaluation environment.