Pharmacophore searching databases

The JME can also serve as a query input tool for structure databases by allowing creation of complex substructure queries (Figure 2-130), which are automatically translated into SMARTS [22]. With the help of simple HTML-format elements the creation of 3D structure queries is also possible, as were used in the 3D pharmacophore searches in the NCI database system [129]. Creation of reac-... 

The 3D pharmacophore search with C(5)ROL in the Biochemical Pathways database provided 13 different molecules as hits. To further limit the number of hits, the additional restriction was imposed that the hits should have only two hydrogen... 

S Wang, DW Zaharevitz, R Sharma, VE Marquez, NE Lewm, L Du, PM Blumberg, GWA Milne. The discovery of novel, stnicturally diverse protein kinase C agonists through computer 3D-database pharmacophore search. I Med Chem 37 4479-4489, 1994. 

Today, 3D databases, which provide the means for storing and searching for 3D information of compounds, are proven to be useful tools in drug discovery programs. This is well exemplified with the recent discovery of novel nonpeptide HIV-1 protease inhibitors using pharmacophore searches of the National Cancer Institute 3D structural database [13-15]. 

As part of the processing within this system, molecules can be cleaned (chirality, ionization). Conformers can also be generated on-the-fly when performing the database search. In addition to conformations, indexing of a database can be done by adding pharmacophore sites. Partial match of the hits on a pharmacophore query is allowed. The pharmacophore search hits are ranked using a fitness function. 

Fig. 14.4 Pharmacophore-based database searching for drug discovery. This example is based on a glucocorticoid receptor dataset (Morgan et al., 2002).

Van Drie, J.H. "Shrink-wrap" Surfaces A New Method for Incorporating Shape into Pharmacophoric 3D Database Searching. J. Chem. Inf. Comput. Sci., 1997, 37, 38-42. 

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