Ligand Database Preparation

When preparing conformational ligand databases, we are interested in maximally leveraging the time required for database preparation and the space required for data storage. Since the data can typically be used for multiple target systems, each with different small-molecule requirements, it is most efficient to tag the compounds with a variety of information. This allows the incorporation of physicochemical properties as well as target- or therapeutic area-specific information (see later sections of this chapter), all of which can be used to select subsets of the compounds for specific purposes. 

A computationally efficient way to search for possible orientations forms the database method. For this protocol a conformational library of the ligand is prepared which is docked rigidly into the binding site. 

As in the case of the protein structure, the use of the correct protonation state is also important when preparing the ligand structures. Alternative structures should be constructed manually and added to the database as individual entities. Stereoisomers and tautomers should be handled similarly. For the construction of tau-... 

Databases such as Enzyme [12], Brenda [5], Ligand [28] and EMP [6] contain enzymes which are involved in a large number of reactions. Each enzyme with known enzyme function are catalogued and named by a nomenclature committee. Also included in the databases is information on the reaction and specificity of the enzyme and the various conditions the enzyme will be active under. Information about the structure and stability of the enzyme and the preparation of the reaction may also be included. 

Ligand preparation and database maintenance can be divided into several subtopics. Ligands need to be represented as chemical data structures. Some ligands may require multiple structures, with comprehensive representation requiring treatment of chirality and/or tautomerization and/or protonation state(s). Dependent on the intended use ofthe database, each structure may further require elucidation of one or more 3D conformers. Each of the resultant representations may then be annotated with various types of information, for example, conformational energy, MW, purchase or synthesis source, and amount of physical compound available. This body of information must then be stored as completely and as compactly as possible. In this section, we explore and comment on some of these aspects of virtual ligand preparation. 

To conduct a ligand-based virtual screening, at least one active query molecule and a search database are required. Section 3.3 discusses the preparation of search databases and the choice of the queries. 

As mentioned in Section 3.1, a ligand-based virtual screening crucially depends on the knowledge of active query molecules, which can either stem from literature or in-house efforts. In some cases, a wealth of information is available, but not all known active compounds are equally suitable queries for virtual screening. The proper choice of the query and the preparation of both the query and the search database will be discussed in the following section. 

As important as the choice of the program and scoring function is the preparation of the ligand stiuctures or the database of potential ligands used for a virtual screening [110]. The protein stiucture must be prepared appropriately as for rigid docking [50]. The question of proper protonation of protein residues should already have... 

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