manual.4.html

最经典的分子对结软件

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Specific Concepts: mechanisms to limit cpu time</H4>
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Sphere Centers</H6>
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From an unknown source:  &quot;...what's good about dock is that it uses spheres; what's bad about dock is that it uses spheres...&quot;</P>
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Spheres are generated to fill the target site. The sphere centers are putative ligand atom positions.  Their use is an attempt to limit the enormous number of possible orientations within the active site.  Like ligand atoms, these spheres touch the surface of the molecule and do not intersect the molecule.  The spheres are allowed to intersect other spheres; i.e. they have volumes which overlap.  Each sphere is represented by the coordinates of its center and its radius.  Only the coordinates of the sphere centers are used to orient ligands within the active site (see above).  Sphere radii are used in clustering.</P>
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The number of orientations of the ligand in free space is vast. The number of orientations possible from all sets of sphere-atom pairings is smaller but still large and cannot be generated and evaluated (scored) in a reasonable length of time.  Consequently, various filters are used to eliminate from consideration, before evaluation, sets of sphere-atoms pairs, which will generate poorly scoring orientations.  That is, only a small subset of the number of possible ligand orientations are actually generated and scored. The distance tolerance is one filter.  Sphere &quot;coloring&quot; and identification of &quot;critical&quot; spheres are other filters.</P>
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Sphere-sphere distances are compared to atom-atom distances.  Sets of sphere-atom pairs are generated in the following manner:  sphere i is paired with atom I if and only if for every sphere j in the set and for every atom J in the set, </P>
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Equation 1</H6>
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where dij is the distance between sphere i and sphere j, dIJ is the distance between atom I and atom J, and e is a somewhat small user-defined value.</P>
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*Note:  since dock matches spheres with ligand atoms by comparing distances between sphere pairs and ligand atom pairs, the mirror image of the ligand atoms (used in the match) may be a better fit, in the rmsd sense, to the spheres, than the atoms of the real, non-mirror-reflected  ligand.  Consider, for example, the distances between the four atoms bonded to a chiral carbon center and the distances between the four atoms bonded to the mirror-image of that chiral carbon center:  the distances are the same, but the two sets of four atoms cannot be superimposed upon one another, unless the chirality of one is reversed.  In a similar manner, the chirality of the ligand atoms used in the match may be opposite to that of the matching spheres.</P>
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Chemical Matching</H6>
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dock spheres are generated without regard to the chemical properties of the nearby receptor atoms.  Sphere &quot;chemical matching&quot; or &quot;coloring&quot; associates a chemical property to spheres and a sphere of one &quot;color&quot; can only be matched with a ligand atom of complementary color.  These chemical properties may be things such as &quot;hydrogen-bond donor,&quot; &quot;hydrogen-bond acceptor,&quot; &quot;hydrophobe,&quot; &quot;electro-positive,&quot; &quot;electro-negative,&quot; &quot;neutral,&quot; etc.   Neither the colors themselves, nor the complementarity of the colors, are determined by the dock suite of programs; dock simply uses these labels. With the inclusion of coloring, only ligand atoms with the appropriate chemical properties are matched to the complementary colored spheres.  It is probably more likely, then, that the orientation generated will produce a favorable score.  Conversely, by excluding colored spheres from pairing with certain ligand atoms, the number of (probably) unfavorable orientations which are generated and evaluated can be reduced. Note that requiring complementarity in matching does not mean that all ligand atoms will lie in chemically complementary regions of the enzyme.  Rather, only those ligand atoms, when paired with a colored sphere which is part of the sphere-atom match, will be guaranteed to be in the chemically complementary region of the enzyme (provided chirality of the spheres is the same as that of the matching ligand atoms).</P>
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Critical Points</H6>
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The &quot;critical point&quot; filter requires that certain spheres be part of the set of sphere-atom pairs used to orient the ligand [<A HREF="Manual.4.html#10407" CLASS="XRef">
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]. Designating spheres as critical points forces the ligand to have at least one atom in that area of the enzyme, where that sphere is located.  This filter may be useful, for example, when  it is known that a ligand must occupy a particular area of an active site. This filter removes from consideration any orientation that does not guarantee at least one ligand atom in critical areas of the enzyme (provided chirality of the spheres is the same as that of the matching ligand atom).</P>
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Scoring Filters</H6>
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After a ligand is oriented within the active site, the orientation is evaluated.  In an attempt to reduce the total computational time, after the ligand is oriented in the site, ligand atoms are first checked to determine whether or not they occupy space already occupied by the receptor. This is often referred to as &quot;bump checking.&quot;  If too many of such &quot;bumps&quot; are found, then the ligand is likely to intersect the receptor even after minimization; consequently, the ligand orientation is discarded before evaluation.</P>
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Caveats</H4>
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In the attempt to balance computational processing time and accuracy, approximations and  simplifications were made to the scoring functions. The interaction energy function, for example, lacks explicit hydrogen-bonding terms, solvation/desolvation terms, or hydrophobicity terms.  More accurate methods do exist for evaluating ligand docking, but at the expense of additional computational time.  dock will do no better than the accuracy of its scoring function.  That is, its ability to predict a novel ligand binding orientation and reproduce a crystal orientation is limited by the accuracy of its scoring function.</P>
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References</H4>
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Kuntz, I.D. Structure-based strategies for drug design and discovery. Science 257: 1078-1082, 1992.</LI>
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Kuntz, I.D., Meng, E.C. and Shoichet, B.K. Structure-based molecular design. Acc. Chem. Res. 27(5): 117-123, 1994.</LI>
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Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E. A geometric approach to macromolecule-ligand interactions. J. Mol. Biol. 161: 269-288, 1982.</LI>
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Shoichet, B.K., Bodian, D.L. and Kuntz, I.D. Molecular docking using shape descriptors. J. Comp. Chem. 13(3): 380-397, 1992.</LI>
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Meng, E.C., Shoichet, B.K. and Kuntz, I.D. Automated docking with grid-based energy evaluation. J. Comp. Chem. 13: 505-524, 1992.</LI>
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6.	<A NAME="25574">
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Meng, E.C., Gschwend, D.A., Blaney, J.M. and Kuntz, I.D. Orientational sampling and rigid-body minimization in molecular docking. Proteins. 17(3): 266-278, 1993.</LI>
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Allen, F.H., Bellard, S., Brice, M.D., Cartwright, B.A., Doubleday, A., Higgs, H., Hummelink, T., Hummelink-Peters, B.G., Kennard, O., Motherwell, W.D.S., Rodgers, J.R. and Watson, D.G. The Cambridge Crystallographic Data Centre: computer-based search, retrieval, analysis and display of information. Acta Cryst. B35: 2331-2339, 1979.</LI>
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Rusinko, A., Sheridan, R.P., Nilakatan, R., Haraki, K.S., Bauman, N. and Venkataraghavan, R. Using concord to construct a large database of 3-dimensional coordinates from connection tables. J. Chem. Info. Comput. Sci. 29: 251-255, 1989.</LI>
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9.	<A NAME="10407">
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DesJarlais, R.L. and Dixon, J.S.  A Shape- and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors.  J. Comput-Aided Molec. Design.  8: 231-242, 1994.</LI>
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