Molecular modelling systematic conformational search

Tel. 415-903-3900, fax 415-961-0584, e-mail support(5)biocad.com Catalyst/Hypo for building molecular models, systematic conformational searching, and statistical fitting of 3D structural features to bioactivities. Phar-macophoric hypotheses can be used to search for matches in databases of 3D structures. Catalyst/Info for managing databases of ID, 2D, and 3D data. Silicon Graphics and networked Macintosh and PCs. 

G-Protein-coupled receptors do not lend themselves to analysis by either NMR or x-ray crystallography due to their structural dependence on an intact cell membrane. In our laboratories we pursued this valuable structural information by utilizing a combination of structural homology modeling, molecular dynamics, systematic conformational searching methods, and mutagenesis experiments. The combination of these techniques led to a proposed model of bradykinin bound to the agonist site on its receptor [41]. 

Molecular model-building (conformational search) methods fall into two general classes systematic and random. - Systematic methods search all possible combinations of torsional angles, whereas random methods usually involve a Monte Carlo (with Metropolis sampling ) or molecular dynamics trajectory. Both approaches attempt to search large areas of conformational space and eventually converge on the desired conformation or structure. Dis-... 

Random sampling, an approach in molecular modeling for conformational energy searching that relies on stochastic probing (Monte Carlo simulation). Different conformations are examined at random - in contrast to systematic searching - in order to explore the conformational space of a molecule. 

Ketoprofen and 17 commonly used excipients were chosen as the probe systems for this study [81]. The molecular modelling has two parts prediction of crystal morphology followed by the prediction of binding energy of a probe molecule on the surfaces of the ketoprofen crystal. Three conformers for each of these excipients (probe molecules) were taken into consideration. For those excipient molecules which have more than one molecule in the asymmetric unit (e.g. sorbitol and a-lactose monohydrate), both the complete asymmetric unit as well as three conformers of a single molecule were considered as the probe conformations for the systematic search study. For those excipients that are polymers, a representative monomer unit was used as a probe molecule. 

Figure 3 Structural alignments with discrete properties. Methods are based on discrete properties using the DG algorithm (1) or clique-detection (11) as implemented in distance comparisons (DISCO), and Apex-3D. The structure representation, based on discrete properties, resorts to one atomic descriptor (I), usually the atom type, or multiple atomic or site descriptors (II). In the first method (I), the conformational analysis is restricted to the generation of molecular geometries which allow a common arrangement of selected phaimacophoric moieties present in a rigid compound used as template. In the second method (II), the conformational analysis procedure may involve a systematic enumeration of all the possible conformadons for each ligand. The search similarity is directed towards the confirmation of a predefined pharmacophore postulated by the modeler or from some classical SAR in the case of the active analog approach (1), or the automated identification of pharmacophores and bioacdve conformations (II)...

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