Distance-geometry Conformation search

Comparative Molecular Field Analysis (CoMFA) Conformational Flexibility in 3D Structure Searching Conformational Sampling Distance Geometry Theory, Algorithms, and Chemical Applications Free Energy Calculations Methods and Applications Free Energy Perturbation... 

Dmparison of various methods for searching conformational space has been performed cycloheptadecane (C17H34) [Saunders et al. 1990]. The methods compared were the ematic search, random search (both Cartesian and torsional), distance geometry and ecular dynamics. The number of unique minimum energy conformations found with 1 method within 3 kcal/mol of the global minimum after 30 days of computer processing e determined (the study was performed in 1990 on what would now be considered a / slow computer). The results are shown in Table 9.1. 

You can often use experimental data, such as Nuclear Overhauser Effect (NOE) signals from 2D NMR studies, as restraints. NOE signals give distances between pairs of hydrogens in a molecule. Use these distances to limit distances during a molecular mechanics geometry optimization or molecular dynamics calculation. Information on dihedral angles, deduced from NMR, can also limit a conformational search. 

Finding the minimum of the hybrid energy function is very complex. Similar to the protein folding problem, the number of degrees of freedom is far too large to allow a complete systematic search in all variables. Systematic search methods need to reduce the problem to a few degrees of freedom (see, e.g.. Ref. 30). Conformations of the molecule that satisfy the experimental bounds are therefore usually calculated with metric matrix distance geometry methods followed by optimization or by optimization methods alone. 

By design, no conformational engine was implemented in DISCO, based on the assumption that at the time, no universal force fields and methods suitable for all types of compounds were available [53]. However, the commercial distributor Tripos provides access to 3D converters and conformational search engines such as Concord and Confort via the Sybyl interface. These algorithms will not be reviewed here as strictly seen they are not part of any pharmacophore identification program. The distance geometry approach has been used... 

DISCO considers three-dimensional conformations of compounds not as coordinates but as sets of interpoint distances, an approach similar to a distance geometry conformational search. Points are calculated between the coordinates of heavy atoms labeled with interaction functions such as HBD, HBA or hydrophobes. One atom can carry more than one label. The atom types are considered as far as they determine which interaction type the respective atom would be engaged in. The points of the hypothetical locations of the interaction counterparts in the receptor macromolecule also participate in the distance matrix. These are calculated from the idealized projections of the lone pairs of participating heavy atoms or H-bond forming hydrogens. The hydrophobic points are handled in a way that the hydrophobic matches are limited to, e.g., only one atom in a hydrophobic chain and there is a differentiation between aliphatic and aromatic hydrophobes. A minimum constraint on pharmacophore point of a certain type can be set, e.g. if a certain feature is known to be required for activity [53, 54]. 

T. F. Havel, I. D. Kuntz, and G. M. Crippen, Bull. Math. Biol. 45, 665 (1983). The Theory and Practice of Distance Geometry. See also A. R. Leach, Reviews in Computational Chemistry, Vol. 2, K. B. Lipkowitz and D. B. Boyd, Eds., VCH Publishers, New York, 1991, pp. 1-55. A Survey of Methods for Searching the Conformational Space of Small and Medium-Sized Molecules. 

Optimal filtering was proposed by Altman and Jardetzky (1989) as a heuristic refinement method of structure determination and has also been applied to the dihedral angle space (KoeU et al., 1992). Optimal filtering uses the exclusion paradigm, and during the search aU possible conformations are retained except where they are incompatible with the data. This allows a more systematic search of the allowed conformational space. As in the case of distance geometry, it is a ptire geometric method, and it calculates the mean positions and standard deviations of each atom. The output also needs to be refined to add information fi om the empirical force field. 

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