Fragment libraries molecule selection

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. 

Lonally, the templates were chosen by trial and error or exhaustive enumeration. A itafional method named ZEBEDDE (ZEolites By Evolutionary De novo DEsign) en developed to try to introduce some rationale into the selection of templates et al. 1996 Willock et al. 1997]. The templates are grown within the zeolite by an iterative inside-out approach, starting from a seed molecule. At each jn an action is randomly selected from a list that includes the addition of new (from a library of fragments), random translation or rotation, random bond rota-ing formation or energy minimisation of the template. A cost function based on erlap of van der Waals spheres is used to control the growth of the template ale ... 

Enumeration is the computational equivalent of carrying out a combinatorial synthesis. The result is a virtual library of product molecules that can then be analyzed using a library design program to select compounds of interest. Two different approaches to library enumeration have been developed fragment marking and the reaction-transform approach (14). 

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