Fragment location methods

The solution to the rigid body problem was to set the values of internal force constant to very large values and use fragments with no torsional degrees of freedom. To treat protein flexibility, a time-dependent Hartree (TDH) approximation is used to normalize the forces on the protein to that of a single fragment. Caflisch et al. 4 applied the multiple-copy, simultaneous search 

Several Monte Carlo (MC) and simulated annealing (SA) approaches have been described that are well suited for determining low energy conformations of molecular fragments and in some cases entire ligands. - Interesting hybrids of MC and SA also have been explored these methods are discussed in the section on whole molecule methods. 

HINT is very useful for providing a straightforward, visual map of the properties of the receptor site. This in turn helps the ligand designer evaluate placement of various functional groups in the receptor. In principle, it also 

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Fragment location methods Determine desirable locations of atoms or small fragments within the active site. 

The slippery slope How should we define a ligand design method For example, are fragment location techniques bona fide de novo design methods or simply a prerequisite for de novo design ... 

Alternate uses Some methods can be adapted for alternatives uses. For example, DOCK, which is clearly a whole molecule approach, also may be viewed as a fragment placement method because it can be used with a library of small fragments to determine optimal locations for those fragments. 

Category 1. Fragment Location (Fragment Placement) Methods... 

Group additivity methods must be derived as a consistent set. It is not correct to combine fragments from different group additivity techniques, even for the same property. This additivity approximation essentially ignores effects due to the location of one functional group relative to another. Some of these methods have a series of corrections for various classes of compounds to correct for this. Other methods use some sort of topological description. 

Molecular ions are usually intense for low-molecular weight compounds. Alkyl cleavage with the charge remaining on the unsaturated portion is very often the base peak. A series of fragment ions with m/z 41, 55. 69, 83, and so forth are characteristic. Methods are available to locate the position of the double bond in aliphatic compounds.1... 

Compound 4 was epoxidized to give 15 (Scheme 3) and the MS fragmentation of 15 is given by the broken-line mlz (relative abundance). To ensure the location of the double bonds, the epoxidation and the MS of 15 was compared with the products of the ozonolysis identified by GC and MS (as marked by the broken lines)6. The use of the various derivatization products via oxidation, combined with other spectroscopic methods, is discussed in Section III. 

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