Volume 1 Chapter 7 Geometric Surveys of Non-Bonded Fragments

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7.14.9 Further Examples of Non-Bonded Searches

The commands available for non-bonded searching provide a very flexible search environment. To conclude this section a number of examples are presented to illustrate how these commands can be combined to answer questions of increasing complexity. These examples also show how the non-bonded search options can be combined with other search features to refine the query, or to perform geometrical surveys.

Ex. 12 Locating all hydrogen bonds in a crystal structure

In section 7.14.2 the INTRA, INTER, and ANY options of CONTACT were used to locate hydrogen bonds of the type

in the entry AAGAGG10. You may have noticed that the crystal structure contained two water molecules. Water can act as both a hydrogen bond donor and acceptor but any potential contacts with these two waters were ignored since we only searched for contacts involving N-H and C=O. It would be interesting to locate and display all hydrogen bonds in the crystal structure. This is possible by combining the ELDEF command with the CONTACT command.

If we use the fragment below, where RR is either nitrogen or oxygen it will be possible to locate all the hydrogen bonds in the crystal structure. First, the VDW-RAD command is used to change the tolerance to 0.0 Å. The ANY option will be used in CONTACT to locate all intramolecular and intermolecular contacts H...N < 2.75Å and H...O < 2.72Å.

  • In constructing the search fragments we use: ELDEF RR = N O

    The complete instruction set is

    VDW TOL 0.0
    CONTACT ANY 5 999 2 A 3 A

    The result of the search is shown below.

    Pharmacophore searches of the database can be conducted by using CONTACT INTRA commands as shown in section 7.14.5 . Because of the crystallographic nature of the CSD it is also possible to search for extended pharmacophores. Extended pharmacophores contain intermolecular contacts in addition to the normal intramolecular contacts.

    The inclusion of intermolecular contacts can provide information about how selected functional groups of the

    pharmacophore interact with various other groups. Geometric data from these contacts can also give some insights into the structure of the target of the pharmacophore. Although only a small number of intermolecular contacts should be used at a time due to the constraints of crystal structures, extended pharmacophore searches can give a new understanding of the pharmacophoric patterns.

    Ex. 13 Consider the pharmacophoric pattern represented by 4 fragments:

    Suppose we wish to find the following non-bonded contacts:

    We also wish to calculate the following geometrical parameters:

    The commands as they appear in the instruction file (including geometric constructs) are:

    GROUP G1 1 2 3 4 5 6
    SETUP X1 1 2 3 4 5 6
    SETUP P1 1 2 3 4 5 6
    CONTACT INTRA 5 8 G1 C 11 A 5.0 6.0
    CONTACT INTER G1 C 8 A 3.0 5.0
    CONTACT INTRA 1 999 9 A 11 A 2.0 4.0
    DEFINE HANG 9 10 8

    Two intermolecular contacts have been added to locate interactions between a carbonyl and the pharmacophoric N-H and aromatic groups. In addition, several geometrical parameters have been defined in order to learn more about the nature of these interactions. One of the resulting hits from this search is shown below.

    HBOND    2.028Å
    HANG   148.507°
    RGDIST   4.864Å
    RGPERP   0.271Å

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    Volume 1 Chapter 7 Commands in the 3D-CONSTRAIN Sub-menu.