Identification, preparation, and characterization of several polymorphs and solvates of terazosin hydrochloride.

The phenomenon of polymorphism is prevalent in pharmaceuticals, yet it is unusual to identify more than three or four forms for any particular drug. Terazosin hydrochloride has been found to exist at room temperature in four solvent-free forms that can be isolated directly, one solvent-free form that can be prepared by desolvation of a methanolate, a methanol solvate, and a dihydrate. This study presents characterization and methods for preparation of each of these forms. Data are also presented demonstrating the relative stability of these forms.

Mapping the N6-region of the adenosine A1 receptor with computer graphics.

N6-substituted adenosine derivatives can be very potent and selective agonists at A1 receptors. The N6-region is usually described by a general model introduced by Kusachi et al. (J. Med. Chem. 1985, 28, 1636). Structure-activity relationships for this region have recently been reported from a detailed study by Daly et al. (Biochem. Pharmacol. 1986, 35, 2467). The N6-region of the A1 receptor was now investigated in further detail with the aid of computer graphics. A map of the N6-region was constructed on the basis of a selected set of data from Daly et al. This map allows Kusachi's model to be extended with two new subregions: a C subregion, accommodating cycloalkyl substituents and a B subregion, which is filled by bulky substituents, such as a norbornanyl moiety. Furthermore, three regions can be distinguished, where occupation leads to diminished receptor affinity, so-called forbidden areas. The extended model permits the contribution of each subregion to be determined quantitatively, allowing accurate prediction of affinities of compounds that were not used to construct the map.

Crystal structure prediction of organic pigments: quinacridone as an example.

The structures of the alpha, beta and gamma polymorphs of quinacridone (Pigment Violet 19) were predicted using Polymorph Predictor software in combination with X-ray powder diffraction patterns of limited quality. After generation and energy minimization of the possible structures, their powder patterns were compared with the experimental ones. On this basis, candidate structures for the polymorphs were chosen from the list of all structures. Rietveld refinement was used to validate the choice of structures. The predicted structure of the gamma polymorph is in accordance with the experimental structure published previously. Three possible structures for the beta polymorph are proposed on the basis of X-ray powder patterns comparison. It is shown that the alpha structure in the Cambridge Structural Database is likely to be in error, and a new alpha structure is proposed. The present work demonstrates a method to obtain crystal structures of industrially important pigments when only a low-quality X-ray powder diffraction pattern is available.

A third blind test of crystal structure prediction.

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

A molecular dynamics approach for the generation of complete protein structures from limited coordinate data.

Generation of full protein coordinates from limited information, e.g., the C alpha coordinates, is an important step in protein homology modeling and structure determination, and molecular dynamics (MD) simulations may prove to be important in this task. We describe a new method, in which the protein backbone is built quickly in a rather crude way and then refined by minimization techniques. Subsequently, the side chains are positioned using extensive MD calculations. The method is tested on two proteins, and results compared to proteins constructed using two other MD-based methods. In the first method, we supplemented an existing backbone building method with a new procedure to add side chains. The second one largely consists of available methodology. The constructed proteins are compared to the corresponding X-ray structures, which became available during this study, and they are in good agreement (backbone RMS values of 0.5-0.7 A, and all-atom RMS values of 1.5-1.9 A). This comparative study indicates that extensive MD simulations are able, to some extent, to generate details of the native protein structure, and may contribute to the development of a standardized methodology to predict reliably (parts of) protein structures when only partial coordinate data are available.

A test of crystal structure prediction of small organic molecules.

A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing, the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as "correct". One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol(-1) of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.