Robin Taylor

Mercury CSD 2.0 – new features for the visualization and investigation of crystal structures

The program Mercury, developed by the Cambridge Crystallographic Data Centre, is designed primarily as a crystal structure visualization tool. A new module of functionality has been produced, called the Materials Module, which allows highly customizable searching of structural databases for intermolecular interaction motifs and packing patterns. This new module also includes the ability to perform packing similarity calculations between structures containing the same compound. In addition to the Materials Module, a range of further enhancements to Mercury has been added in this latest release, including void visualization and links to ConQuest, Mogul and IsoStar.

Mercury: visualization and analysis of crystal structures

Since its original release, the popular crystal structure visualization program Mercury has undergone continuous further development. Comparisons between crystal structures are facilitated by the ability to display multiple structures simultaneously and to overlay them. Improvements have been made to many aspects of the visual display, including the addition of depth cueing, and highly customizable lighting and background effects. Textual and numeric data associated with structures can be shown in tables or spreadsheets, the latter opening up new ways of interacting with the visual display. Atomic displacement ellipsoids, calculated powder diffraction patterns and predicted morphologies can now be shown. Some limited molecular-editing capabilities have been added. The object-oriented nature of the C++ libraries underlying Mercury makes it easy to re-use the code in other applications, and this has facilitated three-dimensional visualization in several other programs produced by the Cambridge Crystallographic Data Centre.

Tables of bond lengths determined by X-ray and neutron diffraction. Part 1. Bond lengths in organic compounds

The average lengths of bonds involving the elements H, B, C, N, O, F, Si, P, S, Cl, As, Se, Br, Te, and l in organic compounds are reported.

Retrieval of Crystallographically-Derived Molecular Geometry Information

The crystallographically determined bond length, valence angle, and torsion angle information in the Cambridge Structural Database (CSD) has many uses. However, accessing it by means of conventional substructure searching requires nontrivial user intervention. In consequence, these valuable data have been underutilized and have not been directly accessible to client applications. The situation has been remedied by development of a new program (Mogul) for automated retrieval of molecular geometry data from the CSD. The program uses a system of keys to encode the chemical environments of fragments (bonds, valence angles, and acyclic torsions) from CSD structures. Fragments with identical keys are deemed to be chemically identical and are grouped together, and the distribution of the appropriate geometrical parameter (bond length, valence angle, or torsion angle) is computed and stored. Use of a search tree indexed on key values, together with a novel similarity calculation, then enables the distribution matching any given query fragment (or the distributions most closely matching, if an adequate exact match is unavailable) to be found easily and with no user intervention. Validation experiments indicate that, with rare exceptions, search results afford precise and unbiased estimates of molecular geometrical preferences. Such estimates may be used, for example, to validate the geometries of libraries of modeled molecules or of newly determined crystal structures or to assist structure solution from low-resolution (e.g. powder diffraction) X-ray data.

A new test set for validating predictions of protein–ligand interaction

We present a large test set of protein–ligand complexes for the purpose of validating algorithms that rely on the prediction of protein–ligand interactions. The set consists of 305 complexes with protonation states assigned by manual inspection. The following checks have been carried out to identify unsuitable entries in this set: (1) assessing the involvement of crystallographically related protein units in ligand binding; (2) identification of bad clashes between protein side chains and ligand; and (3) assessment of structural errors, and/or inconsistency of ligand placement with crystal structure electron density. In addition, the set has been pruned to assure diversity in terms of protein–ligand structures, and subsets are supplied for different protein‐structure resolution ranges. A classification of the set by protein type is available. As an illustration, validation results are shown for GOLD and SuperStar. GOLD is a program that performs flexible protein–ligand docking, and SuperStar is used for the prediction of favorable interaction sites in proteins. The new CCDC/Astex test set is freely available to the scientific community (http://www.ccdc.cam.ac.uk). Proteins 2002;49:457–471.

Three-Dimensional Pharmacophore Methods in Drug Discovery

Andrew R. Leach,* ) Valerie J. Gillet, Richard A. Lewis, and Robin Taylor Computational and Structural Chemistry, GlaxoSmithKline Research & Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Department of Information Studies, University of Sheffield, Regent Court, 211 Portobello Street, Sheffield S1 4DP, U.K., Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland, and Taylor Cheminformatics Software, 54 Sherfield Avenue, Rickmansworth, Herts WD3 1NL, U.K.

Systematic analysis of the probabilities of formation of bimolecular hydrogen-bonded ring motifs in organic crystal structures

A methodology has been developed for characterising hydrogen-bonded ring motifs formed between two organic molecules without any prior knowledge of the topology or chemical constitution of the motifs. The method has been implemented by modifying the current Cambridge Structural Database (CSD) System programs. All intermolecular ring motifs comprising ⩽20 atoms formed with N—H···N, N—H···O, O—H···N and O—H···O hydrogen bonds in organic structures in the CSD have been classified. The 75 bimolecular motifs occurring in >12 structures in the CSD are described in terms of their graph sets and chemical functionalities. Motifs are ranked according to their frequency of occurrence and according to their probabilities of formation, i.e. their frequency relative to the number of possible motifs which could have formed. These probabilities provide insights into the relative robustness of known and potential supramolecular synthons.

IsoStar: A library of information about nonbonded interactions

Crystallographic and theoretical (ab initio) data on intermolecular nonbondedinteractions have been gathered together in a computerised library(’IsoStar‘). The library contains information about the nonbonded contactsformed by some 250 chemical groupings. The data can be displayed visually andused to aid protein–ligand docking or the identification of bioisostericreplacements. Data from the library show that there is great variability inthe geometrical preferences of different types of hydrogen bonds, although ingeneral there is a tendency for H-bonds to form along lone-pair directions.The H-bond acceptor abilities of oxygen and sulphur atoms are highly dependenton intramolecular environments. The nonbonded contacts formed by manyhydrophobic groups show surprisingly strong directional preferences. Manyunusual nonbonded interactions are to be found in the library and are ofpotential value for designing novel biologically active molecules.

Comparing protein-ligand docking programs is difficult.

There is currently great interest in comparing protein–ligand docking programs. A review of recent comparisons shows that it is difficult to draw conclusions of general applicability. Statistical hypothesis testing is required to ensure that differences in pose‐prediction success rates and enrichment rates are significant. Numerical measures such as root‐mean‐square deviation need careful interpretation and may profitably be supplemented by interaction‐based measures and visual inspection of dockings. Test sets must be of appropriate diversity and of good experimental reliability. The effects of crystal‐packing interactions may be important. The method used for generating starting ligand geometries and positions may have an appreciable effect on docking results. For fair comparison, programs must be given search problems of equal complexity (e.g. binding‐site regions of the same size) and approximately equal time in which to solve them. Comparisons based on rescoring require local optimization of the ligand in the space of the new objective function. Re‐implementations of published scoring functions may give significantly different results from the originals. Ostensibly minor details in methodology may have a profound influence on headline success rates. Proteins 2005.

The molecular structures of nucleosides and nucleotides: Part 1. The influence of protonation on the geometries of nucleic acid constituents

Abstract A survey of nucleoside and nucleotide crystal structures using structural data retrieved from the Cambridge Crystallographic Database is presented. The molecular geometries of base residues and terminal phosphate groups in various protonation states have been determined and rationalised by simple valence bond theory. Empirical formulae for inferring the protonation states of base residues and phosphate groups from their molecular dimensions have been derived. The formulae were tested on 43 relatively imprecise crystal structures. The protonation states of 47 out of 51 base residues, and 15 out of 19 terminal phosphate groups, were correctly predicted in the tests.