D Database Searching

For the pharmacophore-based screening, a 3-D-pharmaco-phore feature is constmcted by structure-activity relationship analysis on a series of active componnds (26) or is dednced from the X-ray crystal stmcture of a ligand-receptor complex (27). Taking this 3-D-pharmacophore feature as a query structure, 3-D database search can be performed to select the molecnles from the available chemical databases, which contain the pharmacophore elements and may conform to the pharmacophore geometric constraints. Then the selected compounds are obtained either from commercial sonrces or from organic synthesis for the real pharmacologic assays (see Fig. 3). 

The pharmacophore model obtained by the mapping procedure allows 3-D database searching (Fig. 8). Database searching can identify actives in different chemotypes relative to those utilized for pharmacophore generation. This procedure is often termed as... 

Bohm, H.-J. (1998) Prediction ofbinding constants of protein ligands a fast method for the prioritization of hits obtained from dc novo design or 3 D database search programs. /. Comput. Aid. Mol. Dcs., 12, 309-323. 

K. D. Stewart, S. Loren, L. Frey, E. Otis, V. Klinghofer, and K. I. Hulkoweii Bioorg. Med. Chem. Lett., 8, 529 (1998). Discovery of a New Cyclooxygenase-2 Lead Compound Through 3-D Database Searching and Combinatorial Chemistry. 

H.-J. Bohm,/. Comput.-Aided Mol. Des., 12,309 (1998). Prediction of Binding Constants of Protein Ligands A Fast Method for the Prioritization of Hits Obtained from De Novo Design or 3-D Database Search Programs. 

Y. C. Martin and J. H. van Drie, in Chemical Structures 2 The International Language of Chemistry, W. A. Warr, Ed., Springer-Verlag, Berlin, 1993, pp. 315-326. Identifying Unique Core Molecules from the Output of a 3-D Database Search. 

Y. C. Martin, in Trends in Drug Research, V. Claassen, Ed., Elsevier, Amsterdam, 1993, pp. 129-137. Application of 3-D Database Searching to the Design of Novel Bioactive Compounds. A Case Study with D1 Dopaminergic Agonists. 

Figure 3. Example results for 3-D database search using nicotinic pharmacophore...

Usually the 3-D structure of the enzyme/receptor is not known. In this case, receptor mapping techniques such as CoMFA and conformational analysis techniques such as systematic search and distance geometry are applied to a series of active and inactive structures to obtain a pharmacophore model for use in 3-D database searching. 

As we continued to use 3-D database searching to develop synthetic targets, there was an increasing need to integrate 2-D chemical structure database facilities with molecular modelling facilities (Figure 11). This need, and a desire to provide the synthetic chemist with easily accessible lead discovery and optimisation tools (Figure 12), led us to choose MACCS-3D as our primary 3-D database tool. 

Three-dimensional database searching is a powerful new tool for developing novel synthetic targets. This technique can be used in cases where an enzyme/receptor 3-D structure is known, or alternatively in the case where the enzyme/receptor structure is unknown. In the latter case an active compound or series of compounds can be used to develop a pharmacophore model. Because 3-D database searching requires biological data stored in 2-D databases and molecular modelling techniques, we expect to see increased integration of 2-D and 3-D database/ information systems. 

IDENTIFYING UNIQUE CORE MOLECULES FROM THE OUTPUT OF A 3-D DATABASE SEARCH... 

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