3D Pharmacophore

From DrugPedia: A Wikipedia for Drug discovery

Basic Introduction of 3D Pharmacophore

The traditional medicinal chemistry definition of a pharmacophore is the minimum functionality a molecule has to contain in order to exhibit activity. For a series of derivatives, the molecules usually have much in common and to derive the true minimum pharmacophore, structurally-diverse active molecules are required. Only molecules which interact at the same receptor site in the same way will share a pharmacophore. Consequently, experiments which confirm that competitive binding is occurring can be valuable. In the early stages of a project, when only a few leads are known, it may be worthwhile considering several pharmacophores and selecting molecules to test to reduce the number of possible alternatives.

Software for storing 3D coordinates of molecules has been available for many years. Probably the earliest example of a 3D database system was that developed by Dr Olga Kennard and co-workers at the Cambridge Crystallographic Data Centre which was first published in 1972 [1]. This system has evolved over the years and remains the definitive source of small organic molecule crystal structures. The software includes capabilities to search by geometric constraints as well as connection tables but (of course) does not consider conformational freedom.

3D database technology has emerged as the most important tool for exploiting databases of molecules available for testing. During the 1980's most pharmaceutical companies established 2D databases of compounds they had made and those available for purchase. The availability of software such as CONCORD [2] which automatically created 3D coordinates from the 2D connection tables prompted the development of 3D database software capable of storing and searching a large number of molecules. The 2D databases have continued largely as archival systems whereas companies with 3D databases have been able to use pharmacophore-based queries to select molecules to test