Template-based docking

Structure-based methods utilise information on the 3-D structure of the target protein. This information can be used as a template for docking experiments in which libraries of small molecules are fitted into the binding site of the target. The docking solutions are ranked by means of various scoring functions, leading to a hit list of potential binders. 

The ligand-based alignments were carried out using the superposition program FlexS [2], and compound 4j as rigid template (in the conformation obtained by the docking) on the one site and the Multifit routine within the SYBYL software and the same template on the other site (Fig. 11.5). 

The combinatorial docking tools PRO SELECT [121] and CombiDOCK [122] are based on the incremental construction method. In both approaches, a library is formed by a template (or core) molecule with a set of attachment points to which one out of a predefined set of substituents can be connected. The template is then positioned in the active site without considering the substituents. Starting from a few orientations of the template, the substituents are placed into the active site of the protein independently. In case of PRO SELECT, substituents are then selected based on score and additional criteria like 2D similarity and feasibility of synthesis. CombiDOCK calculates a final score for whole library molecules by combining fragment scores. 

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