Classifying G-protein coupled receptors with bagging classification tree

G-protein coupled receptors (GPCRs) play a key role in different biological processes, such as regulation of growth, death and metabolism of cells. They are major therapeutic targets of numerous prescribed drugs. However, the ligand specificity of many receptors is unknown and there is little structural information available. Bioinformatics may offer one approach to bridge the gap between sequence data and functional knowledge of a receptor. In this paper, we use a bagging classification tree algorithm to predict the type of the receptor based on its amino acid composition. The prediction is performed for GPCR at the sub-family and sub-sub-family level. In a cross-validation test, we achieved an overall predictive accuracy of 91.1% for GPCR sub-family classification, and 82.4% for sub-sub-family classification. These results demonstrate the applicability of this relative simple method and its potential for improving prediction accuracy.     

A new strategy for the design of water-soluble synthetic receptors: specific recognition of DNA intercalators and diamines

Water-soluble zinc bisporphyrin receptors 1 and 2 having two Lewis acidic sites (zinc) in the hydrophobic environment consisting of alkyl chains and a bisporphyrin framework, and covered with hydrophilic exterior (twelve or eighteen carboxyl groups) were prepared. The receptors show high affinity for diamines and DNA intercalators in water where the binding constants K(a) are of the order of 10(7) and 10(8) M(-1), respectively. Diamines and DNA intercalators are bound to the receptor through different mechanisms. Diamines are bound through hydrophobic interactions and zinc-nitrogen interactions, while DNA intercalators are bound through hydrophobic interactions and charge-transfer interactions. Flexible alkyl chains can make van der Waals contact with guests and create a hydrophobic environment around the bound guest by an induced-fit-type mechanism. For the binding of DNA intercalators, the following features are noteworthy: 1). Binding constants are similar between the zinc porphyrins and zinc-free porphyrins; 2). the binding constant is larger for the guest having the lower LUMO; this indicates the important contribution of charge-transfer interactions to binding; 3). the hydrophobic and cationic nature of DNA intercalators is substantially important, and 4). higher ionic strength reduced the binding affinities; this shows a moderate contribution of electrostatic interactions. The conformational instability of the receptors also contributes to the tight binding: hydrophobic and electrostatic interactions cannot both be favorable at the same time in the guest-free receptor. Enthalpy-entropy compensation observed for the binding of diamines and DNA intercalators is characterized by a relatively small slope (alpha=0.74) and a large intercept (beta=7.75 kcal mol(-1)) in the DeltaH degrees versus TDeltaS degrees plot; this shows that a conformational change of receptors and a significant desolvation occur upon binding. The receptor can competitively bind to propidium iodide to deprive DNA of the intercalated propidium iodide. These features of water-soluble receptors consisting of a rigid framework and flexible side chains with a large solvent-accessible area are in contrast to highly preorganized rigid receptors, and they can provide useful guidelines for rational design of induced-fit artificial receptors in water.     

Molecular dynamics of 5-HT1A and 5-HT2A serotonin receptors with methylated buspirone analogues

In the present study experimentally determined ligand selectivity of three methylated buspirone analogues (denoted as MM2, MM5 and P55) towards 5-HT_1A and 5-HT_2A serotonin receptors was theoretically investigated on a molecular level. The relationships between the ligand structure and 5-HT_1A and 5-HT_2A receptor affinities were studied and the results were found to be in agreement with the available site-directed mutagenesis and binding affinity data. Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT_1A/5-HT_2A, each time in a different orientation. Present results were compared with our previous theoretical results, obtained for buspirone and its non-methylated analogues. It was found that due to the presence of the methyl group in the piperazine ring the ligand position alters and the structure of the ligand-receptor complex is modified. Further, the positions of derivatives with pyrimidinyl aromatic moiety and quinolinyl moiety are significantly different at the 5-HT_2A receptor. Thus, methylation of such derivatives alters the 3D structures of ligand-receptor complexes in different ways. The ligand-induced changes of the receptor structures were also analysed. The obtained results suggest, that helical domains of both receptors have different dynamical behaviour. Moreover, both location and topography of putative binding sites for buspirone analogues are different at 5-HT_1A and 5-HT_2A receptors.     

Multivalency as a Chemical Organization and Action Principle

Multivalent interactions can be applied universally for a targeted strengthening of an interaction between different interfaces or molecules. The binding partners form cooperative, multiple receptor–ligand interactions that are based on individually weak, noncovalent bonds and are thus generally reversible. Hence, multi‐ and polyvalent interactions play a decisive role in biological systems for recognition, adhesion, and signal processes. The scientific and practical realization of this principle will be demonstrated by the development of simple artificial and theoretical models, from natural systems to functional, application‐oriented systems. In a systematic review of scaffold architectures, the underlying effects and control options will be demonstrated, and suggestions will be given for designing effective multivalent binding systems, as well as for polyvalent therapeutics.     

Synthesis, activity evaluation and 3D-QSAR study of some novel derivatives of 4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridine

A series of novel derivatives of 4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridine were synthesized and structurally characterized by 1H NMR and MS. Their in vivo anti-platelet aggregation activities were evaluated. A 3D-QSAR was performed using the CoMFA and the CoMSIA. This model provided useful guidelines for novel anti-platelet thienopyridines design.