Crystal blind tests

The state of the art in crystal structure calculation is tested every few years in the crystal structure prediction blind tests organised by the Cambridge Crystallographic Data Centre (CCDC). As of the... 

Several examples of the MOLPAK + WMIN structure prediction procedures are given in the next sections. The problem of identifying the correct crystal structure from literally thousands of possible structures remains. The which is the best/correct solution was an important topic during the 1999 and 2001 CCDC sponsored blind tests [12]. Calculated lattice energies are adequate in many cases, but in others small lattice energy differences make it difficult to separate the wheat from the chaff. Other criteria, such as good or bad patterns of intermolecular contacts in comparison with known crystal structures could be helpful. 

Motherwell WDS, Ammon HE, DunitzJD, Dzyabchenko A, Erk P, Gavezzotti A, Hofmann DWM, Leusen I, LommerseJPM, Mooij WTM, Price SL, Scheraga H, Schweizer B, Schmidt MU, van Eijck BP, Verwem P, and Williams DE. Crystal Structure Prediction of Small Organic Molecules A Second Blind Test. Acta CrystB 2002 B58 647-661. 

Table 1 Overview of programs developed for organic crystal structure prediction by searching for minima in the lattice energy. The types of molecules for which the program was originally developed are given, though all programs with emboldened names were used in the blind tests and so have been used for a wider range of systems (Fig. 4).

Fig. 1 A plot of the lattice energy minima found in the crystal structure prediction search for the rigid CHNO molecule in the 2001 blind test (Fig. 4). in the search by Price. This diagram illustrates the plurality of distinct minima in different space groups found in a relatively sparse search, which did not locate the experimental structure.

Fig. 4 The molecules used in the blind tests of crystal structure prediction, organized by the Cambridge Crystallographic Data Centre in 1999 and 2001. For each molecule, the success rate is given as x/y, where x is the number of successful predictions, and is the number of groups that submitted (usually) three guesses for the crystal Structure.

One approach is to assume that these kinetic factors are in some way represented in experimental crystal structures. Thus, analyses using the information in the Cambridge Structural Database were developed.Although there have yet to be successful independent predictions by this method in the blind tests, this approach holds promise for discriminating among the hypothetical crystal structures within the energy range of potential polymorphism and force field uncertainty. 

The Cambridge Crystallographic Data Centre is thanked for arranging the blind tests, which advanced the area of crystal structure prediction and provided an objective test of the progress. My postgraduate students. Graeme Day and Theresa Beyer, are thanked for providing data for this article. 

For each blind test, recently determined, but unpublished, crystal structures were collected from crystallographers kind enough to delay publication of their structures. From these, a set of molecules were chosen for the test, and their structural diagrams (Table 2.1) were circulated to the participants. The experimentally determined crystal structures were withheld for 6 months by an independent referee, during which time predictions had to be submitted each participant was asked to propose three crystal structures, in order of preference, for each molecule. A prediction was considered to be successful if one of the three submitted structures was an adequate representation of the experimentally determined crystal structure [7]. 

A few things can be said about the overall results of the four blind tests (Table 2.2) there has been some success for rigid molecules, although the predictability of the different category 1 and 2 crystal structures is variable. Molecular flexibility is a serious obstacle for current methods of crystal structure prediction only one category 3 success was achieved in the first three blind tests and, while more success was achieved for the flexible molecule in the latest test, this was partly due to the more restricted molecular flexibility of the molecule chosen that year [19]. 

Table 2.1 Diagrams of the molecules included as targets in the four blind tests of crystal structure prediction... 

Molecule XI was included as an additional category 1 target midway through the 2004 blind test, after it was found that some information on the crystal structure of molecule VIII had been reported. Although most participants continued their predictions without using this experimental information, this molecule might not be considered a true blind test. 

The category of two-component crystals was added to the fourth blind test. 

The improvement in results with more accurate electrostatic models can also be seen by studying the blind test results in more detail. For example, the observed crystal structure of molecule VIII contains molecular tapes based on / (8) hydrogen bond dimers... 

Figure 2.6 Hydrogen bond patterns in the predicted crystal structures of blind test molecule VIII [10]...

Computational assessment of the likelihoods of occurrence and the relative stabilities of polymorphs is not necessarily more effective than the experimental approach. Whilst great advances have been made in the field of ab initio crystal structure prediction (CSP), as documented in five international blind tests spanning the years 1999-2010 [5], it is still not routinely possible to predict whether a molecule is likely to be polymorphic or to confirm whether the most thermodynamically stable structure has been found experimentally, especially for molecules of the complexity of a typical drug. It is possible to compute the polymorph landscape for a specific flexible molecule, but the calculations require considerable expertise, and the timescales and computing resources can render CSP impractical for application to even a limited portfolio of candidate APIs. 

FIGURE 5.4 Molecule XX (benzyl-(4-(4-methyl-5-(p-tolylsulfonyl)-l,3-thiazol-2-yl)phenyl) carbamate) from the fifth blind test of crystal structure prediction, (a) Chemical diagram, (b) overlay of one of the 48 database generated conformations (red) with the conformation in the observed crystal structure, (c) overlay of the CSP global minimum in lattice energy (green) with the observed structure from X-ray diffraction. Source Kazantsev et al. [29]. Reprinted with permission of Elsevier, (see insert for color representation of the figure.)... 

A recent example of such an approach was in the successful prediction of the crystal structure of benzyl-(4-(4-methyl-5-(jo-tolylsulfonyl)-l,3-thiazol-2-yl)phenyl) carbamate, a large, flexible pharmaceutical-like molecule in the fifth CSP blind test (Fig. 5.4) [1, 29], often referred to by its blind test reference nnmber, molecule XX. These blind tests are organized every few years to evalnate the ourent state of CSP methods, by setting a series of molecnles as targets, whose crystal stmctures are withheld until participants have submitted their predictions. Molecule XX was... 

As a final example, we also illustrate how a computational approach was used in a study on possible tautomerism. Molecule VI, studied in the second CCDC blind test [57] may form three different stable polymorphs, aU observed as sidfonimides. However, in one of these forms, a sUght shift in the proton positions within a dimer core of the crystal structure gives the sulfonamide tautomer. Therefore, we initiated a study to elucidate the energy difference between suffonimide and sulfonamide tautomers of VI (Fig. 7.22). 

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