The co-crystals of three industrially important pharmaceutical molecules, the Vitamin B group member nicotinamide (1), the antihyperlipidemic drug clofibric acid (2), and the nonsteroidal anti-inflammatory drug diclofenac (3), are synthesized with the co-crystal former isonicotinamide and characterized by thermal analysis and single crystal X-ray diffraction. Two dimorphic hydrates of isonicotinamide were obtained during the course of these experiments: hydrate 4 (form I) has been reported recently, and hydrate 5 (form II) is new. Both are monohydrates but differ in the number of independent molecules in the asymmetric unit, Z 0 =2 and 8, respectively. Form II is metastable compared to I and converts to form I in the solid state. In all three pharmaceutical co-crystals, it is the pyridine N atom of either the nicotinamide molecule in 1 or the N atom of the isonicotinamide molecule in 2 and 3 that is used in connecting the different molecules together, as a hydrogen bond acceptor from the amine of the isonicotinamide in 1 and the carboxylic acid protons in 2 and 3. The carboxylic acid 3 3 3 pyridine hydrogen bond is an often used supramolecular synthon. A survey of relevant structures in the Cambridge Structural Database of isonicotinamide and nicotinamide co-crystals is given for completeness, and the co-crystal former ability of isonicotinamide and nicotinamide was investigated by performing density functional theory calculations.

Probing the energy landscape and thermodynamics of biomolecules for drug design.

The structures of two major tyrocidines, antibiotic peptides from Bacillus aneurinolyticus, in an aqueous environment were studied using nuclear magnetic resonance spectroscopy, restrained molecular dynamics (MD), circular dichroism, and mass spectrometry. TrcA and TrcC formed β-structures in an aqueous environment. Hydrophobic and hydrophilic residues were not totally separated into nonpolar and polar faces of the peptides, indicating that tyrocidines have low amphipathicity. In all the β-structures, residues Trp(4)/Phe(4) and Orn(9) were on the same face. The ability of the peptides to form dimers in aqueous environment was studied by replica exchange MD simulations. Both peptides readily dimerize, and predominant complex structures were characterized through cluster analysis. The peptides formed dimers by either associating sideways or stacking on top of each other. Dimers formed through sideways association were mainly stabilized by hydrogen bonding, while the other dimers were stabilized by hydrophobic interactions. The ability of tyrocidine peptides to form different types of dimers with different orientations suggests that they can form larger aggregates, as well.

Speciation of ferriprotoporphyrin IX, Fe(III)PPIX, in aqueous solution is complex. Despite the use of its characteristic spectroscopic features for identification, the theoretical basis of the unique UV-visible absorbance spectrum of μ-[Fe(III)PPIX](2)O has not been explored. To investigate this and to establish a structural and spectroscopic model for Fe(III)PPIX species, density functional theory (DFT) calculations were undertaken for H(2)O-Fe(III)PPIX and μ-[Fe(III)PPIX](2)O. The models agreed with related Fe(III)porphyrin crystal structures and reproduced vibrational spectra well. The UV-visible absorbance spectra of H(2)O-Fe(III)PPIX and μ-[Fe(III)PPIX](2)O were calculated using time-dependent DFT and reproduced major features of the experimental spectra of both. Transitions contributing to calculated excitations have been identified. The features of the electronic spectrum calculated for μ-[Fe(III)PPIX](2)O were attributed to delocalization of electron density between the two porphyrin rings of the dimer, the weaker ligand field of the axial ligand, and antiferromagnetic coupling of the Fe(III) centers. Room temperature magnetic circular dichroism (MCD) spectra have been recorded and are shown to be useful in distinguishing between these two Fe(III)PPIX species. Bands underlying major spectroscopic features were identified through simultaneous deconvolution of UV-visible and MCD spectra. Computed UV-visible spectra were compared to deconvoluted spectra. Interpretation of the prominent bands of H(2)O-Fe(III)PPIX largely conforms to previous literature. Owing to the weak paramagnetism of μ-[Fe(III)PPIX](2)O at room temperature and the larger number of underlying excitations, interpretation of its experimental UV-visible spectrum was necessarily tentative. Nonetheless, comparison with the calculated spectra of antiferromagnetically coupled and paramagnetic forms of the μ-oxo dimer of Fe(III)porphine suggested that the composition of the Soret band involves a mixture of π→π* and π→d(π) charge transfer transitions. The Q-band and charge transfer bands appear to amalgamate into a mixed low energy envelope consisting of excitations with heavily admixed π→π* and charge transfer transitions.