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\section{Query Definition}  As a  Getting started  Initiating a Search  A structure can be obtained directly from the PDB by entering its four-character PDB identifier in the first text box after "start from PDB". A list of possible small molecules will be generated automatically in the second box, from which the user may choose a ligand of interest. Binding site waters may be excluded entirely, used as part of the ligand as optional pharmacophore features to include in the similarity search, or used as part of the receptor to identify which pharmacophore features of the ligand are relevant to binding. To proceed with the search, the user should next choose "submit".   Alternatively the user may first choose "enter pharmit search" in order to upload structural files. After being redirected to the search page, choose "Load Features..." to upload a small molecule structure in sdf, pdb, mol2, or xyz format or a pharmacophore query file in MOE, LigBuilder, LigandScout, or Pharmer format. If a receptor is provided, it should be one for which the binding pose of the provided ligand is known, or to which the ligand was previously docked. pharmit will not dock the two compounds, and since the receptor is used to identify which pharmacophore features of the ligand are relevant to binding, providing a pair of structures that are oriented arbitrarily will fail to identify a relevant pharmacophore. The receptor may be provided in sdf, pdb, mol2, or xyz format.  Loading structures  Visualization  After the desired structures are provided, pharmit will identify all pharmacophore features present in the ligand if a ligand structure rather than a pharmacophore query file was provided. If a receptor structure was provided, it will identify which of these features are relevant to the interaction between the protein-ligand pair using distance cutoffs between interacting features and will display only these interacting features. Next, it will center the features and use a set of default visualization options to display the provided structures, including the electrostatic surface of the receptor. If the user is dissatisfied with the default visualization scheme, they may scroll down to the "Visualization" menu in the left sidebar and toggle the options as desired. In particular, if the electrostatic surface of the receptor is obscuring the pharmacophore features, receptor surface opacity may be reduced and at the lowest setting becomes entirely transparent. In the graphical display window, the left mouse button may be used to rotate the scene and the right mouse button or center wheel may be used to zoom. Clicking on spheres - both pharmacophore spheres and shape constraint spheres - toggles between a solid and wire display. In order to maximize the viewable graphical display area, the sidebar may be hidden by pressing the left-pointing arrowhead at the top right of the sidebar. \subsection{Inputs}  The typical starting point for a Pharmit session is a ligand-receptor complex structure. A Pharmit session can be automatically initialized using any such structure available in the PDB by inputing the corresponding PDB ascension code and selecting how active site water molecules should be treated (ignored, as part of the receptor, or as part of the ligand). Alternatively, a user can upload their own complex, in which case the receptor and ligand structures must be in separate files. Any file format supported by OpenBabel \cite{O_Boyle_2011} may be used. Note that the query ligand must be pre-positioned within the binding site of the receptor - Pharmit does not perform docking. It uses the pharmacophore and shape features of a known ligand to screen for novel compounds.  \subsection{Pharmacophore Queries}  A pharmacophore \cite{Koes_2015rev,Yang_2010,Leach_2010} defines the essential features of an interaction, such as hydrogen bond, charged, hydrophobic, or aromatic features. interaction.  Importantly, a pharmacophore includes the spatial arrangement of these features features.   Features supported by Pharmit include hydrogen bond acceptors and donors, negative and positive charges, aromatics,  and hydrophobic features.  As shown in Figure~\ref{mainfig}, a  pharmacophore query specifies these features using tolerance spheres. Matching compounds can be positioned so that their corresponding features are located within these spheres. Some features can have additional constraints, such as direction for hydrogen bonds and aromatics and size (number of atoms) for hydrophobic features.  Pharmacophores are used to define molecular similarity and perform structural alignment. A Pharmit will identify all  pharmacophoredescribes the spatial arrangement of the essential  features of an interaction. Each pharmacophore query feature includes both a type and a radius. The pharmacophore type derives from the underlying chemistry of functional groups and present  inthe context of pharmit may be defined as an aromatic, hydrogen donor, hydrogen acceptor, hydrophobic, negative ion, or positive ion. The set of pharmacophore features chosen to represent  a particular provided  ligand and their geometric orientation structure. If a receptor structure  is used to provided, it will  identify other molecules in a database that also possess that configuration of features. The radius of a pharmacophore query feature determines how closely a molecule in the database must match the configuration which  of these features are relevant to  the query. To be considered similar, protein-ligand interaction using distance cutoffs between corresponding features on  the pharmacophore feature points of receptor and ligand (e.g.,  a molecule in the database must overlap the corresponding pharmacophore feature spheres in hydrogen donor on  the query. The likelihood of this occurring increases with larger feature radius.  A list of pharmacophore features is provided in ligand and acceptor on  the "Pharmacophore" menu in receptor). Only  the sidebar. Pharmacophore interacting  features will be enabled. Alternatively, a pharmacophore query  can be toggled "on" or "off" to include them initialized using pharmacophore files  in MOE, LigBuilder, LigandScout,  or remove them from the search. Pressing the "x" to the right of the pharmacophore removes it from the menu entirely. By pressing the arrow to the left Pharmer query formats. The features  ofa given pharmacophore,  the user query  can vary the type, radius, and location of a pharmacophore, as well as optionally restrict the number of atoms associated with a hydrophobic pharmacophore and be interactively edited within  the phi or psi angle associated with pharmacophore features, such as hydrogen bonds, that have an associated direction. Pharmit interface.  \subsection{Shape Queries}  \cite{matchpack}\cite{vams}  Users have the option of using shape as an additional constraint on the similarity search. The ligand's surface or a set of user-defined spheres may be used as an inclusive constraint, the receptor's surface or a set of user-defined spheres may be used as an exclusive constraint, or both inclusive and exclusive shapes may be used. Multiple spheres may be defined for both inclusive and exclusive search by choosing the "Spheres" option in the dropdown menu and pressing "Add". This will display a menu allowing the user to set the position and size of the sphere. Pressing "Add" again will enable the user to continue adding spheres. The shape constraint is applied differently depending on whether it is used to search the database prior to pharmacophore filtering or to filter results 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. In the latter case, the results of the pharmacophore search are filtered by shape to ensure that at least one heavy atom falls within the inclusive shape and no heavy atom centers fall within any exclusive shape. In either case, the results 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 the aligned pose resulting from the initial search does not meet those constraints. Our recommendation is 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 a pharmacophore search. The order of application of pharmacophore and shape constraints can be swapped using the second button from the top of the left sidebar, which switches between "Pharmacophore Search → Shape Filter" and "Shape Search → Pharmacophore Filter".  \subsection{Visualization}  Next, it will center the features and use a set of default visualization options to display the provided structures, including the electrostatic surface of the receptor. If the user is dissatisfied with the default visualization scheme, they may scroll down to the "Visualization" menu in the left sidebar and toggle the options as desired. In particular, if the electrostatic surface of the receptor is obscuring the pharmacophore features, receptor surface opacity may be reduced and at the lowest setting becomes entirely transparent. In the graphical display window, the left mouse button may be used to rotate the scene and the right mouse button or center wheel may be used to zoom. Clicking on spheres - both pharmacophore spheres and shape constraint spheres - toggles between a solid and wire display. In order to maximize the viewable graphical display area, the sidebar may be hidden by pressing the left-pointing arrowhead at the top right of the sidebar.