The Fragment Approach

Another variation on this technique is to hrst optimize the side chains and then keep the side chains hxed while optimizing the backbone. In an extreme case, representing these hxed side chains as large polygons with some net interaction potential can increase the calculation speed even more. 

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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. 

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. 

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]. 

Results expressed by Eqs (3.100) and (3.102) are strictly valid for ideal systems. Unequal reactivities, substitution effects and the formation of intramolecular cycles will affect them. The first two nonidealities may be conveniently taken into account using the fragment approach described in the previous sections. 

Fattori, D. Molecular recognition the fragment approach in lead generation. Drug Discov. Today 2004, 9, 229-238. 

The rationale for the fragmentation approach is shown schematically in Figure 4. One aliquot of the protein is first treated with trypsin which... 

Commonly used methods are based on fragment constants. The fragmental approaches are based on a simple addition of the lipophilicity of the individual molecular fragments of a given molecule. Three commercially... 

The fragmental approaches can also use information about the 3D structure of molecules. A new version of the KlogP program [86] is based on fragmental indices but it benefits from knowledge of the 3D structure of molecules by means of steric hindrance indices, H, proposed by Cherkasov [87]. The modified equation... 

Bartoli S, Fincham Cl, Fattori D (2006) The fragment-approach an update. Drug Discov Today Technol 3 425 -31... 

Both H2C and H2Si have the same frontier orbitals, denoted by a and 7c. Two possible reaction paths can be considered for the dimerization reaction a least-motion path where both molecules approach each other in a plane and a non-least-motion path where at large distances the fragments approach each other in perpendicular planes (Figure 46). 

F. Fragmentation Approach In actual practice, the fragmentation approach affords rather complete flexibility to the ligand and subsequently, bind them at the appropriate target site. 

Thus, both fragment-based and whole-molecule-based approaches require approximations. The fragment approach assumes that a diverse set of substituents will yield diverse libraries. The whole-molecule approach is very slow and also assumes that similarity can be adequately characterized by very crude computations. This chapter focuses on the fragment-based approach, calculating properties on the substituents only, the site of attachment being replaced by a dummy atom. 

Ludi Ludi [17] is a product of Acceliys (Insight II) which can be used in both stmc-ture-based dmg design (protein structure is known) and ligand-based drug design (protein stmcture is not known). Based on this, it mns in two modes receptor mode and active analog mode. This mainly follows the fragment approach where initially... 

Syntheses of LH-RH/FSH-RH (or more simply, LRH) quickly followed the structural elucidation and a typical e.xample contributed by Folkers and colleagues has been delineated in Chart 9. Other total syntheses of LRH by the fragmentation approach or by solid phase techniques have been reported within a few months of one another. LRH has been synthesized employing the SP approach with a benzhydrylamine polymer and both [[2-Gly]LRH and des-2-His-LRH have been prepared by the same general method. A description of the polymer and general experimental approach has been summarized in the first part of Chart 13 in Chapter 14. 

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