Conformationally flexible searching

ChemDBS-3D uses rule-based systematic conformational analysis (single = 3, alpha 4, double/conjugated = 2 points) or random rule-based (max. time 2 min), or flexifit (no VDW bump check) ISIS/3D and UNITY use torsional minimization (conformationally flexible searching and directed tweak, respectively. 

Once the search has completed and the resultant hits have been identified, the final function is their presentation to the user. While commonly the search engine is responsible, separate specialized modules may be involved. The two most commonly exercised options are interactive browsing and printed reports, and they are commonly used in precisely that order. When browsing, it is useful to understand how the query was fitted to the molecule currently being displayed most software provides an overlay and colored highlight capability for this visualization. When browsing lists produced by conformationally flexible searches, the 3D model may be displayed in the conformation which was computed to satisfy the query geometry. 

In all of the 3D search methods the conformational flexibility creates considerable difficulties. Large databases of multiple conformations for each structure have been developed which make the solution of this problem possible. 

Bcl-2 is one of the many factors that control apoptosis, and overexpression of Bcl-2 has been observed in many different cancers. A homology model of Bcl-2 was derived from the NMR 3D structure of the Bcl-XL complex with a Bak BH3 peptide. This model served to search the NCI 3D database of 206,876 organic compounds for potential Bcl-2 inhibitors, which bind to the Bak BH3 binding site of Bcl-2. Full conformational flexibility of the ligands was taken into account in the program DOCK. Thirty-five potential inhibitors were tested, and seven of them had IC50 values from 1.6 to W.OpM. One of... 

Chemithon film sulfonating-sulfating systems, 23 544-547 Chemithon reactor, 23 544 Chemoinformatics, 6 1-25 chemical databases, 6 19-20 chemical information retrieval, 6 6—19 chemical information storage, 6 2-6 chemical library design, 6 17-18 clustering techniques, 6 16-17 conformational flexibility, 6 10-11 conformational searches, 6 10-11 data analysis and preparation, 6 20-21 data searching, 6 6-19 diversity searches, 6 14-18... 

Virtual screening applications based on superposition or docking usually contain difficult-to-solve optimization problems with a mixed combinatorial and numerical flavor. The combinatorial aspect results from discrete models of conformational flexibility and molecular interactions. The numerical aspect results from describing the relative orientation of two objects, either two superimposed molecules or a ligand with respect to a protein in docking calculations. Problems of this kind are in most cases hard to solve optimally with reasonable compute resources. Sometimes, the combinatorial and the numerical part of such a problem can be separated and independently solved. For example, several virtual screening tools enumerate the conformational space of a molecule in order to address a major combinatorial part of the problem independently (see for example [199]). Alternatively, heuristic search techniques are used to tackle the problem as a whole. Some of them will be covered in this section. 

Hahn, M. (1997) Three-dimensional shape-based searching of conformationally flexible compounds. / Chem Inf Comput Sci 37, 80-86. 

ChemCore module to three-dimensionalize 2D structures, interfaces to reformat MACCS, SMILES, or DARC-2D databases, ChemDBS-1 module to build 3D databases, and ChemDBS-3D module to search 3D databases. Database searching accounts for conformational flexibility while storing only one conformation. Chapman 8c Hall s 3D Dictionary of Drugs (12,000 medicinally interesting compounds), 3D Dictionary of Natural Products (50,000 antibiotics, alkaloids, and terpenoids), and 3D Dictionary of Fine Chemicals (105,000 organics). 

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