Geometric search

FIGURE 16.3 (cont d). Output from the CSD. (c) Molecular formula and three-dimensional diagrams generated from search, (d) Geometric searches leading to, for example, histograms of comparisons of numerical output. Courtesy the Cambridge Structural Database. 

Brint AT, Willett P. Pharmacophoric pattern matching in files of three-dimensional chemical structures comparison of geometric searching algorithm. J Mol Graph 1987 5 49-56. 

Y. C. Martin, Tetrahedron Comput. Methodol., 3, 15 (1990). Computer Design of Potentially Bioactive Molecules by Geometric Searching with ALADDIN. 

A 3D geometric search is then performed to look for relationships between features in a molecule. The initial 2D pattern search takes into account only the composition of the molecule, such as atom types and bond types. The 3D portion is only concerned with the geometric relations between the features (e.g., distance, angle, exclusive van der Waals volume, overlapping van der Waals volume, and constraints). A 3D search makes use of the coordinates stored in the database for determining whether constraints are satisfied. 

Many of the false matches are eliminated by the distance search. The co-ordinate data for each structure which passes the screen search are retrieved from a disk file, the exact interatomic distances are calculated, and then compared with the set of query distances to determine whether all of the latter are present within the structure. The co-ordinate data are very bulky, and require access to backing storage for each of the molecules involved in the distance search. In addition, there is the computation associated with the calculation of the distances and their subsequent comparison with the set of query distances thus the distance search is much more time-consuming than the screen search, despite the much smaller number of structures that needs to be processed. While the distance search permits the identification of those structures which contain the precise distances in the query specification, it does not involve consideration of the overall topography of the structures, which can only be established by the final geometric search (which is discussed in detail in a later section). 

Table 1 Numbers of structures matching in the screen search (SS), distance search (DS) and geometric search (GS) for ten published pharmacophoric patterns.

Set reduction involves the successive elimination of candidate structure atoms from sets corresponding to each pattern atom on the basis of an analysis of neighbourhood and connectivity information. The technique has been widely used as a component of 2-D substructure searching systems and we have developed a modification of the technique which can be used for geometric searching. The first stage of the algorithm involves the creation of a distance table. The NQ pattern atoms are labelled from 1 to NQ and for each of the NQ(NQ-l)/2 distinct interatomic distances in the pattern (or less if not all of the query distances are specified for the search), a list of pairs of atoms from the structure is produced. The distance between the atoms in these pairs is equal to that between the pattern atoms (to within any specified tolerances), and the atom type of the first atom corresponds with the type of the first query atom (and similarly for the second atom). 

Brint, A.T. Willett, P. Pharmacophoric Pattern Matching in Files of 3-D Chemical Structures Comparison of Geometric Searching Algorithms . J. Mol. Graphics. In the press. 

Design processes of new products often use existing parts e.g. to reduce production costs. To find parts which fit to the new needs e.g. a geometrical search has to be performed. This could be done by using JT-datasheets. 

The geometric search program, GSTAT, provides facilities to pose a va-... 

In the systems at Pfizer, the molecules that pass the screens are carried onto the distance search and the geometric search. This is necessary since a struaure that matches the query at the screen level may not be a match, either because the screens refer to distance ranges and not to precise distances, or... 

---