Conformational analysis structural databases

Tel. 703-461-7078, fax 703-451-6639, e-mail esIone masoni.gmu.edu Conformational analysis with molecular mechanics. Graphical display of output from AMPAC. Databases of octanol/water partition coefficients for 2500 compounds and 1500 3D structures. 2D-to-3D structure conversion. PCs. 

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). 

Low energy conformations of the Ala-cisPro-Tyr peptide that display a c/sproline-aromatic interaction were found by structural database analysis and systematic search (see section 3 and Figure 3). In order to know whether these conformations are stable in water on a 100 ps time scale, five MD simulations started from the conformations al-3 and bl-2 were performed. The same MD protocol as for the long MD simulations was used, with 100 ps equilibration time and 100 ps data acquisition time. 

Allen, F. H., Doyle, M. J., and Taylor, R. Automated conformational analysis from crystallographic data. 3. Three-dimensional pattern recognition within the Cambridge Structural Database System implementation and practical examples. Acta Cryst. B47, 50-61 (1991). 

Database Prediction of / -tum loop type by sequence in comparison to conformational analysis of / turns in structures 59 loops Correct prediction of turn type in 47/59 cases (80%). 

L. E. Donate, S. D. Rufino, L. H. J. Canard, T. L. Blundell. Conformational analysis and clustering of short and medium size loops connecting regular secondary structures A database for modeling and prediction. Prot. Science. 1996, 5, 2600-2616. 

Molecular docking and structural alignment methods are based on three-dimensional structures of candidate molecules that can be generated by rule-based methods such as CORINA [13, 14] or CONCORD [15]. However, methods based on three-dimensional structures are computationally quite demanding and cannot routinely be applied to databases of hundreds of thousands of compounds today. For this reason, a number of fast methods to determine molecular similarity have been developed that operate solely on connectivity and atom types of molecules. Such tools allow rapid prescreening of very large databases and avoid a conformational analysis of each candidate molecule. 

The X-ray crystal structure database led us to believe that peptide bonds adopt either the cis or trans conformation in native proteins [22,128]. However, NMR spectroscopy [143], and in a few cases, crystal structure analysis [144], provide encouraging experimental evidence of conformational peptide bond polymorphism of folded proteins. Furthermore, conformational changes in response to ligand binding, crystallization conditions and point mutations at remote sites are frequent. Consequently, the three-dimensional protein structure database contains homologous proteins that have different native conformations for a critical prolyl bond [12]. 

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