Fragments Screen Searching

Fragment screening by NMR was applied recently in the search of non-peptidic small molecule inhibitors. Two scaffolds (13) and (14), which bind the enzyme at the S1-S3 and the S2 binding site respectively, as shown by chemical shift perturbation, were linked together to yield competitive inhibitors such as (15) with micromolar IC50 values [158]. There have been no reports of non-peptidic inhibitors with potency and pharmacokinetics similar to the peptidic or peptidomimetic inhibitors described above. 

Gannon MT, Willett P. Sampling considerations in the selection of fragment screens for chemical substructure search systems. J Chem Inf Comput Sci 1979 19 251-255. 

An extension of SOCRATES to handle chemical reactions, called CONTRAST, has also been developed at Sandwich, again with some collaboration from Peter Willett at Sheffield. In SOCRATES the precursors of our company compounds are stored in the compound registry file, and so application of a reaction site detection algorithm to the starting material and product generates a set of modified connection tables and fragment screens, and a set ofreaction bit-screens. The substructure search graphical structure input menu was modified to enable the chemist to identify the atoms involved in the reaction, but otherwise is essentially the same interface as in SOCRATES. 

Several parameters of the procedure can be varied, and all have been exhaustively evaluated and compared the methods adopted in the operational system reflect the best solutions to emerge from these evaluations, with some compromises to improve efficiency. The standard set of 1315 fragment screens, chosen on frequency grounds for use in SOCRATES substructure searching, is used as the structural features, and only presence/absence information, rather than occurrence counts, is used. The Tanimoto... 

Screens traditionally denote the presence or absence of predefined atom-, bond-, or ring-centered substructural fragments. However, one may also use subgraphs of the molecules to generate a set of molecular fingerprints to use as the screen. The screen search checks each structure for those screens present in the query substructure. For maximum effeaiveness the fragments included should occur independently and with equal frequency in the database. " ... 

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