User-defined fragments

Figure 7.7 Combinatorial molecule assembly scheme. Resultant candidate molecules are objects that have building-blocks attached to scaffolds via linkers. Three user-definable fragment sets are needed to feed the algorithm with fragments for each domain. A few example fragments of each type are shown for clarity. For virtual library enumeration, each database fragment gets linked to each other fragment following a combinatorial assembly scheme.

Pre- or user-defined fragments are called up by pressing the respective function key. The size and the orientation of the fragment on the screen is defined by positioning fragment atoms 1 and 2 with the mouse cursor. 

User-defined fragments. These fragments have lipophilic increments defined by the user. 

Next, custom software is used to interrogate the deconvoluted data set to identify the protein s mass and the intensity of the peak, determine any potential modification above a user-defined intensity threshold and, if there is a hit, calculate the mass and the relative conjugation of the fragment. In fact, the percent conjugation is used as a measure of relative affinities of the fragment hits. Since the library is mass encoded (all compounds in a well have a unique mass), the calculated mass of any hits are queried into a database to identify their structures. 

Usually this method is used on an H-depleted molecular graph, truncated expansions being obtained considering only fragments up to a user-defined size. Some methods for -> log P estimations are based on cluster expansion. Moreover, a new method for the calculation of embedding frequencies for acyclic trees based on spectral moments of iterated line graph sequence was proposed recently [Estrada, 1999]. 

Empirical descriptors can be a few user-defined values for discriminating among special molecular fragments or counting local specific atom/fragment occurrences within a molecule. 

In the prioritization step, all remaining structures that have not been rejected in the selection step are scored using the function described in section 8.3. It is possible to specify a lower limit for the score. LUDI will then accept only those structures with a score better than the user-defined threshold value. In addition, LUDI also tries to estimate the possible maximum score for each fragment (assuming a fully buried surface and the formation of hydrogen bonds with all polar groups of the fragment). The ratio actual score/possible maximum score can also be used as a selection criterion. 

Finally, the various cyclical and acyclical conformational fragments are combined. Those conformations that have an internal energy lower than a user-defined value are submitted to a geometry optimization step of the open-chain portions by applying the empirical energy function. Additionally, van der Waals potentials are used to avoid steric crowding or atom clashes. Furthermore, energetically and structurally identical and quite similar conformations are rejected. 

The program is able to calculate a wide variety of internal coordinates for each fragment located in the search procedure. The subset of parameters required for a particular study is entirely under the control of the user. Each individual parameter is specified in terms of the (user-defined) atomic enumeration of the fragment. Three major commands, DEFine, SETup and TRAnsform are used to specify geometrical parameters. 

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