Validation of Pharmacophore Models

The validity of pharmacophore models that overlay the classical can-nabinoids and AAIs has been brought into question by recent mutation work on the CBi receptor. It was found that mutation of Lys-192 in the third... 

Validation of Pharmacophore Models to Guide Medicinal and Computational Chemistry... 

Another retrospective analysis of already known H DAC inhibitors was carried out by You et al. [68]. They generated a 3D chemical-feature-based pharmacophore model and compared the ligand-based model with the structural-functional requirements for the binding of the HDAC inhibitors. Using this model, the interactions between the benzamide MS-275 and HDAC were explored. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme-inhibitor interaction pattern identified from molecular docking. However, also in this study no experimental validation of the modeling results was provided. 

All these facts lead to the conclusion that our new five-feature pharmacophore model should be a good abstract representation of the most important structural elements that a compound should possess for high a1(j adrenoceptor affinity. Similarity between the HBA and PI features of the pharmacophore model with parts of the theoretical receptor could be also considered as an additional validation of our model. 

Returning to the definitions of pharmacophore (Box 1), one of the most direct methods to validate a pharmacophore model is to show its consistency with the interaction pattern that known ligands exhibit with the targeted protein site. 

Albeit very prudent, Ghose and Wendoloski suggested the use of a biophysical data source to determine the conformation of the free ligand as another means to validate a pharmacophore model [45]. After all, when one has no other data to start with, why would one discard it ... 

The pharmacophore derived by Hibert et al. [58] by superimposition of antagonists of different structural classes contains the same elements as the agonist pharmacophore, namely an aromatic ring and a basic nitrogen atom. As might be expected, the special requirements differ from the agonist pharmacophore d= 5.6 A and h= 1.6A. Unfortunately, the model was built with only moderately active compoimds. For validation of this model more SARs of the concerning classes should become available. 

Schuster, D., Laggner, C., Steindl, T.M. and Langer, T. (2006) Development and validation of an in silico P450 profiler based on pharmacophore models. Current Drug Discovery Technologies, 3, 1—48. 

Validation of Antitarget Pharmacophore Models 6.3.3.1 Virtual Screening Hit Rates and Yields... 

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