Fragment approach

This basic LFER approach has later been extended to the more general concept of fragmentation. Molecules are dissected into substructures and each substructure is seen to contribute a constant inaement to the free-energy based property. The promise of strict linearity does not hold true in most cases, so corrections have to be applied in the majority of methods based on a fragmentation approach. Correction terms are often related to long range interactions such as resonance or steric effects. 

Octano/—Water Partition Coefficient. The Fragment approach (234—236) has been reviewed (227) and another method similar to the UNIFAC refit for Henry s constant has been proposed. Improved accuracy for many species and the abiUty to correct for temperature effects have been claimed for the newer method. 

An acceptable reconciliation of inherent flaw and fracture energy concepts has not been achieved and provides an area of current study. The two theoretical concepts will be discussed, and several applications in fragment-size prediction will be described. We will make comparisons between the two fragmentation approaches and attempt to identify some conditions which determine when one or the other method applies. 

How is this different from what s In place now (10 minutes) Systematic vs. fragmented approach... 

R. F. Rekker and R. Mannhold, Calculation of Drug Lipophilicity. The Hydrophobic Fragmental Approach, VCH, Weinheim, 1992, p. 112. 

In many respects the fragment approach is ideally suited to projects which have X-ray crystal structures available. The fragments are small and relatively weak binders, but they often only possess one pharmacophoric element that binds to a specific feature on the target. If this interaction is identified by X-ray structure determination, then project teams can propose specific plans which maintain that critical interaction, and ideally optimize binding through other vectors in their fragments. 

HCV IRES (Table 1, entry 6) A mass spectroscopy-based fragment approach was used to identify the weak binder 29 to the ribosome HA sub-domain of hepatitis C (HCV IRES). Conventional optimisation led to a sub-micromolar lead 30 [41]. 

One advantage of this response of molecular fragment approach [24] to condensed Fukui functions is that Equations 18.21 through 18.24 are easily evaluated from the population analysis data that accompanies the output of most quantum chemistry calculations. 

There are minimal experimental data available for the R component of drug-like compounds. However, the quantification of the Rj component can be approximated using different methods or fragmental approaches. Fragments can be classified... 

In designing preparative radical ionic chain reactions, including the fragmentation approach to alkene radical cations, careful choice of the radical... 

In a rare example of the use of phenylselenides as radical precursors in the generation of alkene radical cations by the fragmentation approach, Giese and coworkers generated a thymidine C3/,C4/ radical cation by expulsion of diethyl phosphate. Trapping experiments were conducted with methanol and with allyl alcohol (Scheme 16), when nucleophilic attack was followed by radical cyclization [66]. 

For a tandem Diels-Alder/fragmentation approach to the eleutherobin aglycone, Winkler et al. used Marshall s protocol in an early step of the synthesis. The building block 95 was prepared in that way (Scheme 15.24) [56]. 

In the traditional molecular-fragment approach the coefficients of the vector components are usually binary- or positive integer-valued. A continuous vector representation can be constructed in the following way. Choose a set of/molecular fragments, or whole molecules, as a molecular basis for representing chemistry space... 

The [4+2] fragments approach is surely the most explored and hitherto used procedure to construct pyridazine, phthalazine, and cinnoline rings. CHEC(1984) <1984CHEC(2)1> as well as CHEC-II(1996) <1996CHEC-II(6)1> covered many examples. We decided to follow the same subdivision as CHEC-II(1996) to cover this area. 

Hubbard, R. E. (2008) Fragment approaches in structure-based drug discovery. J Synchrotron Radiat 15, 227-230. 

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