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\section{Search}  Pharmit provides two search modalities depending on whether the pharmacophore or search query is the primary query. In both cases, the primary query determines the pose alignment of the hit compounds and the secondary query serves as an additional filter.  \subsection{Pharmacophore/Shape Search}  If the primary query is the pharmacophore query, the selected database searched for compounds that match the specified pharmacophore using the Pharmer \cite{Koes_2011} search technology. Results are aligned to the pharmacophore to minimize the root mean squared deviation (RMSD) between the query features and the hit compound features. Results are sorted with respect to this pharmacophore RMSD.  If a shape query is also present, then the shape constraints are applied to the pharmacophore aligned pose. Search  In this modality, only heavy atom centers are compared to the shape constraints. That is, the pharmacophore-aligned results are filtered to ensure that hits have at least one heavy atom center that falls within the inclusive shape and no heavy atom center that falls within the exclusive shape. With this modality, the exclusive shape is generally the most useful, as it provides a way to eliminate compounds that match the pharmacophore but have significant steric clashes with the receptor. Due to the importance and increased specificity of the interactions specified by a pharmacophore, pharmacophore search followed by shape filtering is the default and recommend search modality.  \subsection{Shape/Pharmacophore Search}  If the primary query is the shape query, VAMS \cite{vams} is used to search a shape index  \cite{matchpack} for matches. In this case, all molecules are pre-aligned to their moments of inertia and hits are aligned to the moments of inertia of the query. Molecular shapes are computed using the solvent excluded volume and are stored at a 0.5{\AA} resolution. A shape matches the query if, in its aligned position, the entirety of the inclusive shape constraint is contained within the shape while no part of the shape overlaps the exclusive shape. This is a more stringent requirement than that which is imposed when the shape query is used as a filter to a pharmacophore search.  Matching compounds are sorted with respect to their Tanimoto shape similarity with of the query ligand.  The shape constraint If a pharmacophore query  is applied differently depending on whether present,  it is used tosearch the database prior to pharmacophore filtering or to  filterresults returned by a pharmacophore search. In the former case, a shape search returns molecules in the search database that contain the entire included shape and do not overlap any part of  the excluded shape. shape-aligned results.  In the latter this  case, theresults of the  pharmacophore search are filtered by shape to ensure that at least one heavy atom falls within features of  the inclusive shape and no heavy atom centers hit compound must  fall withinany exclusive shape. In either case,  the results tolerance spheres  of the initial search are aligned to that search for the secondary filtering - thus for a given molecule a pose may exist that allows it to meet the secondary filter, but it will not be returned if pharamacophore query with  the aligned pose resulting from compound in  the initial search does not meet those constraints. Our recommendation is shape-aligned pose. That is, a compound  that users define both inclusive and exclusive shape constraints using the ligand and receptor surfaces and use them as secondary filtering on the results of would match  a pharmacophore search. The order of application of pharmacophore and shape constraints can be swapped using the second button from query if  the top of query were  the left sidebar, which switches between "Pharmacophore Search → Shape Filter" and "Shape Search → Pharmacophore Filter". primary query may still be filtered out.    \subsection{Filters}  Additional hit reduction and screening options are provided in the "Filters" menu. The three options for hit reduction include restricting the maximum hits returned for every configuration, for every molecule, and overall. The maximum hits per configuration constraint is applied greedily, returning the first n results found without prioritizing any other aspects of those results. The other two constraints are applied after the results are sorted, giving priority to those of higher rank (lower RMSD for pharmacophore searches and higher similarity scores for shape searches). There are seven options given for hit screening. These include constraints on molecular weight, the number of rotatable bonds, LogP (a measure of lipophilicity), polar surface area (indicative of ability to permeate cell membranes), the number of aromatic groups, the number of hydrogen bond acceptors, and the number of hydrogen bond donors. Properties are computing using OpenBabel.