Multiple pharmacophores

Sorich MJ, Miners JO, McKinnon RA, Smith PA. Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substrate selectivity. Mol Pharmacol 2004 65 301-8. 

For targets that lack structural information, such as GPCRs or ion channels, a pharmacophore model or multiple pharmacophore models for different series of compounds can explain SAR and guide the synthesis of new analogs. Alternatively, homology models based on bacteriorhodopsin have been used to explain the interactions of small molecules with GPCRs. 

Figure 15. 3- and 4-point multiple pharmacophore overlaps for the thrombin ligand MQPA and the serine protease active-site derived pharmacophores the left-side arrow indicates the incorrect indication of factor Xa selectivity from the 3-point figures, and the right-side arrow the observed activity and the increased resolution of selectivity using the 4-point relative pharmacophores. 

Scaffold proposals were collected and reviewed according to privileged ion channel motifs, chemical feasibility, and fit to our multiple pharmacophores. Building block selection, virtual library design, and filtering yielded small virtual libraries suitable for automated solution-phase synthesis. All synthesized compounds were finally purified and characterized prior to addition to our focused library. 

Figure 4 The multiple pharmacophore concept from a single molecule...

A rapid computational method for lead evolution has been described by the CombiChem (now DeltaGen) group (39). Their 3D computational approach for lead evolution is based on a pharmacophore fingerprint approach using multiple pharmacophore hypotheses. A set or ensemble of is generated that is... 

The use of pharmacophoric descriptors in enhancing the hit-to-lead properties of lead optimization libraries has been described (76). Pharmacophore fingerprints, based on the Chem-X/ChemDiverse multiple pharmacophore descriptors, were used and several issues in the design of lead optimization libraries were addressed. The applicability of... 

Li, W.X., Li, L., Eksterowicz, J., Ling, X.B. and Cardozo, M. (2007) Significance analysis and multiple pharmacophore models for differentiating P-glycoprotein substrates. Journal of Chemical Information and Modeling, 47, 2429-2438. 

Cottrell, S. J., Gillet, V. J., Taylor, R., Wilton, D. J. Generation of multiple pharmacophore hypotheses using multiobjective optimisation techniques. J. Comput.-Aided Mol. Des. 2004,18, 665-682. 

Methods to deal with the fundamental problem of inference (i.e., multiple pharmacophores being consistent with a typical SAR). 

Befitting the notion that these are fully automated pharmacophore discovery methods, this is minimal, although DISCO, Hiphop, and Catalyst s HypoGen require considerable user intervention to sift through the multiple pharmacophores that emerge. Furthermore, considerable effort is advocated in selecting a representative dataset for HypoGen to avoid nonsensical results. 

Instead of applying additional filtering mechanisms on a hit list, one can evaluate the quality of the pharmacophores to be used as 3D search queries beforehand. The assessment of the quality of a 3D pharmacophore will strictly depend on the main objective(s) of the project (coverage and/or selectivity and/or enrichment). To evaluate one or multiple pharmacophores, one requires a test database that contains i) multiple families of molecules (diverse in structure and type of activity) and ii) a clear activity annotation (if possible with the molecular mechanism of action). Giiner and Henry [44] have developed a series of indices that can be calculated for multiple pharmacophores in order to make an informed decision about the one to be used to screen a virtual library or a corporate collection. 

Distance Comparison for multiple pharmacophores generations, Based on clique detection. The conformational search is separated. 

Structure Complex, multiple pharmacophores Simple, single pharmacophore... 

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