Conformational richness and multiple Z' in salt co-crystal of N-methylpiperidine betaine with N-methylpiperidine betaine hexafluorosilicate.

The co-crystal structure of N-methylpiperidine betaine with N-methylpiperidine betaine hexafluorosilicate represents an unusual case of a salt co-crystal with a high Z' value (3), unexpected conformational variability, and with nearly 50% of its contents disordered. The betaine units from the salt and co-crystal formers are paired into several homoconjugated dimers via very short, linear O(-)...H(+)...O(-) bridges. These hydrogen bonds are the dominating interactions in the co-crystal structure, in variance with the simple hexafluorosilicate salt, which has a structure governed by COOH...F hydrogen bonds. The SiF(2-)(6) anion in the co-crystal structure has only C-H...F interactions with the betaine units. The zwitterion:cation:anion stoichiometry is 3:3:1.5. Some of the betaine units display disorder, but each case is different. One of the SiF(2-)(6) anions is ordered while possessing exact crystallographic symmetry. The other one is disordered in a general position. In addition, there are three water molecules in the crystal structure. One is fully ordered, one has an H atom disordered in two positions and the third one occupies two alternative positions with unequal populations.

Protein kinase inhibitors: structural insights into selectivity.

Protein kinases are involved in many diseases like cancer, inflammation, cardiovascular disease, and diabetes. They have become attractive target classes for drug development, making kinase inhibitors as important class of therapeutics. The success of small-molecule ATP-competitive kinase inhibitors such as Gleevec, Iressa, and Tarceva has attracted much attention in the recent past. Kinases make use of ATP for phosphorylation of a specific residue(s) on their protein substrates. More than 400 X-ray structures of about 70 different kinases are publicly available. These structures provide insights into selectivity and mechanisms of inhibition. However, prediction of binding specificity of kinase inhibitors based on structural information alone appears to be insufficient. Here, we will review these observations to gain insights into the rules that govern protein kinase inhibitor selectivity.

Evaluation of glycolamide esters of indomethacin as potential cyclooxygenase-2 (COX-2) inhibitors.

A number of novel indomethacin glycolamide esters were synthesized and tested for their cyclooxygenase (COX-1 and COX-2) inhibition properties in vitro. Many of these compounds proved to be selective COX-2 inhibitors, and subtle structural changes in the substituents on the glycolamide ester moiety altered the inhibitory properties as well as potencies significantly. Their in vitro data were rationalized through molecular modeling studies. Few of them displayed anti-inflammatory activity in vivo. Compound 32, [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetic acid 2-morpholin-4-yl-2-oxo ethyl ester, was identified as a promising compound in this class and its good anti-inflammatory activity was demonstrated in the in vivo model.

3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were carried out on quinazoline, quinoline, and cyanoquinoline derivatives inhibiting c-Src kinase. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed. The conventional r2 values for CoMFA and CoMSIA are 0.93 and 0.89, respectively. In addition, a homology model of c-Src kinase with the activation loop resembling the active conformation was constructed using the crystal structure of the kinase domain of Lck. The ATP binding pocket of the active form of c-Src is similar to that of the c-Abl kinase in which the activation loop resembles that of an active form. One of the potent c-Src and c-Abl dual kinase inhibitors (77 or SKI-606) was docked inside the active sites of both c-Src and c-Abl. The orientation and hydrogen bonding interactions of 77 are similar in both kinases. The results of 3D-QSAR analyses and structure based studies will be useful for the design of novel c-Src and c-Abl dual kinase inhibitors.

3D-QSAR CoMFA, CoMSIA studies on substituted ureas as Raf-1 kinase inhibitors and its confirmation with structure-based studies.

Three-dimensional quantitative structure activity relationship (3D-QSAR) analyses were carried out on 91 substituted ureas in order to understand their Raf-1 kinase inhibitory activities. The studies include Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Models with good predictive abilities were generated with the cross validated r2 (r2cv) values for CoMFA and CoMSIA being 0.53 and 0.44, respectively. The conventional r2 values are 0.93 and 0.87 for CoMFA and CoMSIA, respectively. In addition, a homology model of Raf-1 was also constructed using the crystal structure of the kinase domain of B-Raf isoform with one of the most active Raf-1 inhibitors (48) inside the active site. The ATP binding pocket of Raf-1 is virtually similar to that of B-Raf. Selected ligands were docked in the active site of Raf-1. Molecule 48 adopts an orientation similar to that inside the B-Raf active site. The 4-pyridyl group bearing amide substituent is located in the adenosine binding pocket, and anchored to the protein through a pair of hydrogen bonds with Cys424 involving ring N-atom and amide NH group. The results of best 3D-QSAR model were compared with structure-based studies using the Raf-1 homology model. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for activity of this class of molecules as Raf-1 inhibitors. Based on these results, novel molecules with improved activity can be designed.

Hydrogen-bond networks in tris(4-hydroxyphenyl)methane and its 1:1 molecular complex with 4,4'-bipyridine.

In tris(4-hydroxyphenyl)methane (or 4,4',4"-methanetriyltriphenol), C(19)H(16)O(3), molecules are connected by O-H.O hydrogen bonds [O.O = 2.662 (2) and 2.648 (2) A] into two-dimensional square networks that are twofold interpenetrated. In tris(4-hydroxyphenyl)methane-4,4'-bipyridine (1/1), C(19)H(16)O(3).C(10)H(8)N(2), trisphenol molecules form rectangular networks via O-H.O [O.O = 2.694 (3) A] and C-H.O [C.O = 3.384 (3) A] hydrogen bonds. Bipyridine molecules hydrogen bonded to phenol moieties [O.N = 2.622 (3) and 2.764 (3) A] fill the voids to complete the structure.

Supramolecular synthons based on N-H...N and C-H...O hydrogen bonds. Crystal engineering of a helical structure with 5,5-diethylbarbituric acid.

5,5-Diethylbarbituric acid is a convenient molecular precursor for a newly identified N-H...N/C-H...O synthon, which is robust enough for the design of a helix architecture.

Atomic resolution structure of squash trypsin inhibitor: unexpected metal coordination.

CMTI-I, a small-protein trypsin inhibitor, has been crystallized as a 4:1 protein-zinc complex. The metal is coordinated in a symmetric tetrahedral fashion by glutamate/glutamic acid side chains. The structure was solved by direct methods in the absence of prior knowledge of the special position metal centre and refined with anisotropic displacement parameters using diffraction data extending to 1.03 A. In the final calculations, the main-chain atoms of low B(eq) values were refined without restraint control. The two molecules in the asymmetric unit have a conformation that is very similar to that reported earlier for CMTI-I in complex with trypsin, despite the Met8Leu mutation of the present variant. The only significant differences are in the enzyme-binding epitope (including the Arg5 residue) and in a higher mobility loop around Glu24. The present crystal structure contains organic solvent molecules (glycerol, MPD) that interact with the inhibitor molecules in an area that is at the enzyme-inhibitor interface in the CMTI-I-trypsin complex. A perfectly ordered residue (Ala18) has an unusual Ramachandran conformation as a result of geometrical strain introduced by the three disulfide bridges that clamp the protein fold. The results confirm deficiencies of some stereochemical restraints, such as peptide planarity or the N-C(alpha)-C angle, and suggest a link between their violations and hydrogen bonding.

Topological equivalences between organic and coordination polymer crystal structures: an organic ladder formed with three-connected molecular and supramolecular synthons.

[structure: see text] Crystal engineering of an organic ladder can be achieved with a T-shaped molecule, 4,4-bis(4'-hydroxyphenyl)-1-cyclohexanol, having three hydroxyl functionalities that can form O-H...O hydrogen-bonded helices. The topology of this network structure finds a parallel in three-connected coordination polymers.