Fragment connection methods

Methods in this category include the early algorithms of Dean, Lewis, Leach et al., CAVEAT,HOOK, SPLICE and related programs, NEWLEAD, PRO LIGAND, 06- 7 ELANA,i and the artificial intelligence approach of Cohen and Shatzmiller.i In addition, there are various 3D database methods  

Fragment connection methods use databases of a variety of types. Databases taken directly from libraries of known compounds include the Cam- 

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Fragment connection methods Start with previously positioned fragments and find linkers or scaffolds to connect those fragments and hold them in a desirable orientation. 

Figure 3 Schematic picture of fragment connection methods.

Figure 4 Problems that may be encountered with fragment connection methods.

There are several advantages to sequential buildup procedures. First, because each fragment is selected based on its ability to contribute to receptor binding, the ligands suggested by these methods should in principle be smaller and more efficient than molecules derived from fragment connection methods. Second, because each piece is added sequentially, it is possible to perform more detailed conformational analyses, leading to fewer misses. ... 

Estimation from molecular connectivity index/fragment contribution method (Meylan et al. 1992, Lohninger 1994) ... 

They found the former considerably better, since their molecular connectivity model had R2 = 0.765 with a mean error of 0.440 log units. It should be noted that the R2 value of 0.967 for their fragmental constant method is so high that overfitting has probably occurred, since the error on measured log Koc values is quite high (Nendza, 1998). 

Figure 2. Schematic representation of fragment linkage methods. In A a tricyclic ring linker connects three previously placed key fragments avoiding bumping the receptor. In B a bump occurs (signalled by the arrow).

In the molecular connectivity method a series of indexes is developed, expressing structure information at several levels. The molecular skeleton is conceived as consisting of fragments of different sizes and complexity. The molecular graph may be decomposed into fragments called subgraphs, such as a skeletal bond, a pair of adjacent bonds, a cluster of bonds to a central atom, etc. 

Site point connection methods Determine desirable locations of individual atoms ( site points ) and then place fragments within the active site so that those locations are occupied by suitable atoms. 

Random connection methods A special class of techniques combining some of the features of fragment connection and sequential buildup methods, along with bond disconnection strategies and ways to introduce randomness. 

Low ionizing potentials or soft ionization methods are necessary to observe the parent ions in the mass spectra of many S-N compounds because of their facile thermal decomposition. Mass spectrometry has been used to investigate the thermal breakdown of S4N4 in connection with the formation of the polymer (SN). On the basis of the appearance potentials of various S Ny fragments, two important steps were identified ... 

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