Recognition pharmacophore

The Novartis group used the X-ray structure of a Grb2-peptide complex [68] as the structural basis for a design attempt that yielded entirely new non-peptide SH2 domain ligands [164]. As mentioned several times throughout this contribution, the interaction of the pTyr sidechain and the Asn sidechain in pTyr+2 position of the peptide ligand have been identified as key elements for molecular recognition (see Fig. 10). The obvious relevance of these two sidechain functionalities allowed the definition of a minimal pharmacophore pattern that... 

Characterization of the GABAa Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling... 

The quantitative comparison of the optimized 3D structure of a selected set of ligands allows the development of their minimal 3D structural requirements for the recognition and activation of the biological target, that is, the pharmacophore hypothesis, and gives a sound 3D rationale to the available SARs [21]. A more complete and mechanistically relevant approach to the development of the 3D pharmacophore consists in its translation into a numerical molecular descriptor that quantifies the molecular-pharmacophore similarity-diversity for computational QSAR modeling [21,41]. 

The overall procedure is called MetaSite (site of metabolism prediction) [32]. The M IF calculations, pharmacophoric recognition, descriptor handling, similarity computation, reactivity computation, inhibition and subselectivity are calculated automatically once the ligand compound(s) is(are) provided. The complete calculation is performed in few seconds in IRIX Linux or Windows environments. 

M., Wildgoose, M., Giesing, D., Fravolini, A., Cruciani, G. and Vaz, R.J. (2005) A pharmacophore hypothesis for P-glycoprotein substrate recognition using GRIND-based 3D-QSAR. Journal of Medicinal Chemistry, 48, 2927-2935. 

Van drie, J.H., Weininger, D., and Martin, Y.C. ALADDIN an integrated tool for computer-assisted molecular design and pharmacophore recognition from geometric, steric, and substructure searching of three-dimensional molecular structures./. Comput.-Aided Mol. Des. 1998, 3, 225-251. 

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