Ligand bioactive conformation

This chapter summarizes the computational methodologies used for conformational analysis. Specifically, Section 8.1 gives a theoretical outUne of the problem and presents details of various implementations of computer codes to perform conformational analysis. Section 8.2 describes calculations illustrative of the current accuracy in generating the conformation of a ligand when bound to proteins (the bioactive conformer) by comparisons to crystaUographically observed data. Finally, Section 8.3 concludes by presenting some practical... 

Figure 8.5 shows for different values of the duphcate removal parameter - the number of ligands for which the OMEGA conformation reproduces the bioactive conformation. It can be seen that the value of the duplicate removal parameter has a significant effect on the ability to reproduce the experimental bioactive conformation. Low values of the -rms parameter reproduce greater than 65% of the bioactive conformations, whereas for high values the number converges to approximately 30%. 

Certain computational methodologies such as some approaches to quantitative structure-activity relationship (QSAR) studies use 3D ligand structures [37, 38]. These methods generally assume that a bioactive conformation has been estab-Hshed for a set of molecules and that these conformers can be ahgned in a maimer that reflects the relative orientation they would adopt in a binding site. It is thus... 

Weide T, Modlinger A, Kessler H (2007) Spatial Screening for the Identification of the Bioactive Conformation of Integrin Ligands. 272 1-50 Weiss EA, Wasielewski MR, Ratner MA (2005) Molecules as Wires Molecule-Assisted Movement of Charge and Energy. 257 103-133... 

Blommers MJJ, Strauss A, Geiser M, Ramage P, Sparrer H, Jahnke W (2008) NMR-Based Strategies to Elucidate Bioactive Conformations of Weakly Binding Ligands. 273 1-14 Blum LJ, see Marquette CA (2005) 261 113-129... 

Spatial Screening for the Identification of the Bioactive Conformation of Integrin Ligands... 

If the bioactive conformation of a ligand for a particular receptor is known, then a single three- or four-point 3D pharmacophore that is crucial for the... 

The above examples of peptide scaffold- or nonpeptide template-based peptidomimetic agonists or antagonists illustrate various strategies to elaborate bioactive conformation and/or pharmacophore models of peptide ligands at their receptors. In many cases, receptor subtype selectivity has also been achieved by systematic structural modifications of prototypic leads of peptidomimetics. Thus, although the 3D structures of G-protein-coupled receptors (GPCRs) remain as elusive (except for models constructed from homology-based low-... 

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