PrGen: Pseudoreceptor Modeling Using Receptor-mediated Ligand Alignment and Pharmacophore Equilibration
✍ Scribed by Peter Zbinden; Max Dobler; Gerd Folkers; Angelo Vedani
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 1998
- Tongue
- English
- Weight
- 156 KB
- Volume
- 17
- Category
- Article
- ISSN
- 1868-1743
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✦ Synopsis
Based on the structures of known ligand molecules, a pseudoreceptor modeling concept developed at our laboratory allows the construction of a peptidic binding-site model for a structurally uncharacterized bioregulator. Such a threedimensional receptor surrogate Ð validated using an external set of test compounds Ð should be able to semiquantitatively predict the binding af®nities of related molecules. To reduce problems resulting from the mutual obscuring of functional groups within a pharmacophore hypothesis, we have devised a procedure referred to as receptor-mediated ligand alignment. It permits to identify an alternate position, orientation and conformation for each ligand molecule by means of conformational search within a primordial receptor model, constructed about the most potent ligands of a series. To derive an energetically relaxed model with a high correlation between calculated and experimental free energies of ligand binding, we have developed a ligand equilibration protocol. During this iterative procedure, the receptor surrogate and the pharma-