Fragment-based

In principle, two different classes of structure generators can be distinguished, namely empirical approaches,. such as fragment-based or rule- and data-based... 

The program system COBRA [118, 119] can be regarded as a rule- and data-based approach, but also applies the principles of fragment-based (or template-based) methods extensively (for a detailed description sec Chapter 11, Sections 7.1 and 7.2 in the Handbook). COBRA uses a library of predefined, optimized 3D molecular fragments which have been derived from crystal structures and foi ce-field calculations. Each fi agment contains some additional information on... 

D structures can be generated with fragment-based, data-based, and numerical methods. 

A particularly good selection of physical properties may be spectra, because they are known to depend strongly on the chemical structure. In fact, different types of spectra carry different kinds of structural information, NMR spectra characterize individual carbon atoms in their molecular environment. They therefore correspond quite closely to fragment-based descriptors, as underlined by the success of approaches to predict NMR spectra by fragment codes (see Section 10.2.3). 

A proper representation of the molecular structure is crucial for the prediction of spectra. Fragment-based methods, topological descriptors, physicochemical descriptors, and 3D descriptors have been used for this endeavor. 

GROUPBUILD [68] fragment-based, sequential growth, combinatorial search ... 

PRO-SELECT [77] fragment-based, scaffold-linker approach ... 

SKELGEN [78] smaU-fragment based, Monte-Carlo search ... 

The central 10 base pairs of the palindromic DNA molecule have a regular B-DNA structure. Between base pairs 5 and 6 in each half of the fragment (base pairs are counted from the center) there is a 40° kink which causes these base pairs to be unstacked (Figure 8.24a). After this localized kink the two end regions have an essentially B-DNA structure. The kink occurs at a TG step in the sequence GTG. These TG steps at positions 5 and 6 are highly conserved in both halves of different CAP-binding sites, presumably in part because they facilitate kinking. 

Poly(arylene oxides) with heterocyclic fragments based on new types of activated difluoroaromatic compounds 99MI18. 

Boehm H-J. Fragment-based de novo ligand design. Proceedings of the Alfred Benzon Symposium No. 39,1996. p. 402-13. 

Although such a fragment-based measure clearly provides a very simple picture of the similarity relationships between pairs of structures, it is both efficient (because it involves just the application of logical operations to pairs of bit-strings) and effective (in that it is able to bring together molecules that are judged by chemists to be structurally similar to each other) in operation. 

As the availability of crystal structures increased in the early 1990s, a number of experimental and computational methods were developed to use the structure of the protein target as a route to discover novel hit compounds. The methods include de novo design, virtual screening, and fragment-based discovery. These developments are covered in more detail in the later chapters of this book, but their main features can be summarized as follows. 

Zartier ER, Shapiro MJ. Fragonomics fragment-based drug discovery. Curr Opin Chem Biol 2005 9 366-70. 

Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H. Fragment based lead discovery using x-ray crystallography, J Med Chem 2005 48 403-13. 

Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. I Med Chem 2000 43 3714-7. 

The most significant differences between TPSA and 3D PSA were observed for large macrocycles containing many polar substituents These substituents are usually buried in the center of the ring and are therefore not accessible to solvent. Fragment-based TPSA provided larger values than 3D PSA in such cases. 

Descriptors used to characterize molecules in QSAR studies should be as independent of each other (orthogonal) as possible. When using correlated parameters there is an increased danger of obtaining non-predictive, chance correlation [56]. To examine the correlation between PSA (calculated according to the fragment-based protocol [10]) and other descriptors, we studied a collection of 7010 bioactive molecules from the PubChem database [57]. In addition to PSA, the following parameters were used ... 

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