Fragment-based methods

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 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. 

The simplest method is based on the total kinetic energy of the fragments ... 

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. 

In this chapter, we describe substructure-based logP calculation approaches comprising fragmental and atom-based methods property-based approaches are discussed in Chapter 15. 

The DFT/COSMO calculations are the rate-limiting part of the method and can easily take a few hours for molecules with up to 40 heavy atoms on a 3-GHz computer [36]. To overcome speed limitations, the authors developed the COSMOfrag method. The basic idea of this method is to skip the resource-demanding quantum chemical calculations and to compose a profiles of a new molecule from stored a profiles of precalculated molecules within a database of more than 40000 compounds. A comparison of the full and fragment-based versions for log P prediction was performed using 2570 molecules from the PHYSPROP [37]. RMSE values of 0.62 and 0.59 were calculated for the full COSMO and COSMOfrag methods, respectively [36]. 

Rotstein SH, Murcko MA. GroupBuild a fragment-based method for de novo drug design. J Med Chem 1993 36 1700-1710. 

Jahnke, W., Erlanson, D.A. (Eds) Fragment-Based Approaches in Drug Discovery. Vol 34 in series Methods and Principles in Medicinal Chemistry (Series Eds R. Mannhold, H. Kubinyi, G. Folkers). Weinheim, Germany Wiley-VCH 2006. 

Researchers at Sunesis pharmaceuticals have developed a fragment-based drug discovery method termed tethering [25]. The approach, which is illustrated in Scheme 2.6, shares a number of features with DCC. Whereas protein-directed DCLs equilibrate small molecules via disulfide formation, say, in the presence of a protein that acts as a thermodynamic trap, tethering uses a cysteine residue on the protein surface to reversibly capture small-molecule thiol fragments from solution. Tethering is designed... 

Richards, N., Williams, P. B., and Tute, M. (1991) Empirical methods for computing molecular partition coefficients. I. Upon the need to model the specific hydration of polar groups in fragment based approaches. Int. J. Quant. Chem. 18, 299-316. 

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