Application of pharmacophores

Pharmacophore modeling in computer-aided drug design is generally applied in three domains. The first is the definition of relevant pharmacophoric features in a drug molecule necessary to achieve a certain biological effect and to estabhsh clear SARs. A well-developed pharmacophore 

To end up with a predictive pharmacophore model, it is necessary to start with reliable structural and biological data. First of all, it is important to have correct 3D structures of all compounds under study. Thus, atomic valences, bond orders, protonation state and stereochemistry have to be checked carefully. Also the consideration of different possible tautomers is necessary when the bioactive form is not exactly known. Another prerequisite is the existence of a similar binding mode of all ligands under study. Experimental data, from competition experiments or protein-ligand crystal structures, can clearly point out that the ligands interact with the same binding epitope in a similar way and not on distinct binding sites. 

Conformational analysis of ligand molecules and bioactive conformation 

Since molecules are flexible and not static, a conformational analysis has to be carried out first to generate an ensemble of low-energy conformations. This is probably one of the most critical steps in the pharmacophore discovery process, since the goal is not only to consider the global minima of a molecule, but also to include the bioactive conformation as part of an ensemble of low-energy conformations. 

Under physiological conditions (T = 310K), the free energy (in kcal/mol) and the binding affinity are related by  

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Application of Pharmacophore Fingerprints to Structure-based Design and Data Mining... 

VI. Combined Applications of Pharmacophore, Molecular Modeling and MO Calculations... 

VI. COMBINED APPLICATIONS OF PHARMACOPHORE, MOLECULAR MODELING AND MO CALCULATIONS... 

Manetti, F., Botta, M., Tafi, A. Application of pharmacophore models in medicinal chemistry. In Pharmacophores and Pharmacophore Searches (Langer, T., Hoffmann, R. D., Eds). Wiley-VCH Weinheim, 2006, pp. 253-282. 

The application of pharmacophore-based screening of chemical databases has led to the discovery of several synthetic leads for promising drug targets. The following two application examples represent a typical structure-based and ligand-based pharmacophore modeling study, respectively. 

Karnachi, P. and Kulkarni, A. (2006) Application of pharmacophore fingerprints to structure-based design and data mining, in Pharmacophores and Pharmacophore Searches (eds T. Langer and R.D. Hoffmann), Wiley-VCH Verlag GmbH, Weinheim, pp. 193-206. 

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