Virtual Screening Using Fingerprints Part I. A Hybrid Approach to Pharmacophore Point Perception
About 90% of drug targets cannot be crystallized. If the 3D structure of the active site is not available, a pharmacophore model is created. Such models are typically based on compounds that are known to bind to the target receptor. When creating pharmacophore models (either in 2D or in 3D) the pharmacophoric characteristic of known actives, as well as of candidates tested, have to be recognized.
The presentation gives an overview about the creation of pharmacophore models and perceptions. One possible approach to create pharmacophore models from 2D structures is to count frequencies of all atom-based pharmacophore point pairs with respect to their topological distance. On the other hand the rule based pharmacophore perception focuses on the molecules that are localized to moieties of the structure, defining whether the pharmacophore type of an atom will be a donor or an acceptor by rule. However, this perception has got two major problems: (1) large number of rules are needed to cope with exceptions; (2) different pH implies different rules. In the following section of the presentation the method of the hybrid approach for pharmacophore perception is thoroughly explained with its new rule-base and with results. The pharmacophore perception is implemented within ChemAxon's JChem software tool.