MESPEUS: a database of metal coordination groups in proteins.

MESPEUS is a freely accessible database which uses carefully selected metal coordination groups found in metalloprotein structures taken from the Protein Data Bank. The database contains geometrical information of metal sites within proteins, including 40 metal types. In order to completely determine the metal coordination, the symmetry-related units of a given protein structure are taken into account and are generated using the appropriate space group symmetry operations. This permits a more complete description of the metal coordination geometry by including all coordinating atoms. The user-friendly web interface allows users to directly search for a metal site of interest using several useful options, including searching for metal elements, metal-donor distances, coordination number, donor residue group, and structural resolution. These searches can be carried out singly or in combination. The details of a metal site and the metal site(s) in the whole structure can be graphically displayed using the interactive web interface. MESPEUS is automatically updated monthly by synchronizing with the PDB database. An investigation for the Mg-ATP interaction is given to demonstrate how MESPEUS can be used to extract information about metal sites by selecting structure and coordination features. MESPEUS is available at http://mespeus.nchu.edu.tw/.

The Defeathering Effect by Scalding in Chickens Follows Their Intrinsic Dermal Histologies.

This study aimed to delineate the fundamental skin histology and its association with feathers in broilers and native Red-Feather (RF) chickens and further elucidate their thermal alterations in respect to the defeathering effect by scalding. Comparisons of skin thickness between fresh samples and those after dehydration and fixation, as well as their collagen contents and histological differences, suggested that RF chickens had a thicker dermal layer with more collagen deposition and compact architecture, particularly in the neck and abdominal skin, but a thinner hypodermal layer in the back, chest, and abdomen skin. Despite an adolescent age, RF chickens showed a shorter calamus depth of tail feathers but a larger calamus diameter of wing feathers. Within the feather follicle punch, a very intense follicle sheath layer with compact collagenous matrixes to fulfill the space next to the inner feather root sheath was observed in RF chickens. Under both soft and hard scalding, RF chickens showed a lower degree of denaturation on hip skins and were more resistant to structural disintegration, primarily within the epidermal and dermal layer. Accordingly, a much narrower gap space between the feather sheath and surrounding follicle sheath was observed, and the gap expansion was also resistant to thermal changes. These results suggest that the defeathering effect by scalding follows the intrinsic skin histologies in chickens of various breeds and ages, primarily depending on the interaction of the feather calamus with the surrounding follicle sheath and neighboring cutaneous tissues, reflecting their resistance to thermal denaturation, but is irrelevant to the feathers per se.

Modulating the affinity and signaling bias of cannabinoid receptor 1 antagonists.

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or ß-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or ß-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge.

Effects of Hard and Soft Scalding on Defeathering and Carcass Quality of Different Breeds of Chickens.

Current soft scalding in broilers is not applicable to various strains of chickens with different market weights and ages. This study aimed to examine the effectiveness of soft (57 °C for 120 s) and hard (60 °C for 60 s) scalding on defeathering and carcass quality of the local strain of Red Feather (RF) country chickens and determine age, breed, and body weight factor in accounting for the defeathering effectiveness using adult layers and juvenile broilers as a reference. Results showed no differences between soft and hard scalding in broilers with 60% and 80% of acceptable defeathering scores, respectively, while a significantly better effect by hard scalding was observed in adult layers, young and old RF chickens with more than 70% of birds exhibiting desirable scores and less than 20% by soft scalding. In contrast to soft scalding, hard scalding had no significant effects on breast meat color but impaired skin color in broilers as assessed by L*, a*, and b* value analysis. Interestingly, hard scalding increased breast skin yellowness and lightness in young RF chickens and lightness in old RF chickens, while there were no significant changes in layers. However, hard scalding decreased skin elasticity in layers and old RF chickens. The effectiveness of defeathering by scalding method was governed by the age to reach a certain threshold in the development of dermal architecture and feather richness, irrelevant to body weight. The alteration of carcass color primarily depends on age, body weight/breed, and their interaction. In conclusion, current soft scalding is suitable for broiler chickens for desirable defeathering effect and carcass color, whereas layers and RF chickens scaled at 60 °C for 60 s showed a better defeathering effect without unfavorable changes of breast meat and skin color.

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.

A structure-function approach identifies L-PGDS as a mediator responsible for glucocorticoid-induced leptin expression in adipocytes.

Leptin is an adipokine predominantly secreted by adipocytes and has many physiological roles, including in energy homeostasis. We identified that AM630, a cannabinoid receptor 2 (CB2) antagonist, down-regulated leptin expression in mature adipocytes differentiated from either stromal vascular fractions isolated from inguinal fat pads of C57BL/6J mice or 3T3-L1 preadipocytes. However, the leptin-suppressive effects of AM630 preserved in CB2-deficient adipocytes indicated the off-target activity of AM630 in leptin expression. Pharmacological and genetic studies, cheminformatics, and docking simulation were applied to identify the potential protein target of AM630 that modulates leptin expression in differentiated primary preadipocytes. Screening of the reported off-targets of AM630 identified a synthetic cannabinoid WIN55212-2 exerting the same function. Target deconvolution and docking simulation suggested that AM630 and WIN55212-2 were both inhibitors of lipocalin-type prostaglandin D2 synthase (L-PGDS). Further studies showed that L-PGDS positively regulates leptin expression. Although glucocorticoid and aldosterone were previously reported to induce expression of both L-PGDS and leptin, our data demonstrated that L-PGDS mediates only glucocorticoid-induced leptin expression in differentiated primary preadipocytes. No effect was observed after aldosterone treatment. This newly discovered glucocorticoid - L-PGDS - leptin pathway may provide insights into current clinical use of glucocorticoid and management of their undesired effects such as obesity.

systemsDock: a web server for network pharmacology-based prediction and analysis.

We present systemsDock, a web server for network pharmacology-based prediction and analysis, which permits docking simulation and molecular pathway map for comprehensive characterization of ligand selectivity and interpretation of ligand action on a complex molecular network. It incorporates an elaborately designed scoring function for molecular docking to assess protein-ligand binding potential. For large-scale screening and ease of investigation, systemsDock has a user-friendly GUI interface for molecule preparation, parameter specification and result inspection. Ligand binding potentials against individual proteins can be directly displayed on an uploaded molecular interaction map, allowing users to systemically investigate network-dependent effects of a drug or drug candidate. A case study is given to demonstrate how systemsDock can be used to discover a test compound's multi-target activity. systemsDock is freely accessible at http://systemsdock.unit.oist.jp/.

Identification of potential inhibitors based on compound proposal contest: Tyrosine-protein kinase Yes as a target.

A search of broader range of chemical space is important for drug discovery. Different methods of computer-aided drug discovery (CADD) are known to propose compounds in different chemical spaces as hit molecules for the same target protein. This study aimed at using multiple CADD methods through open innovation to achieve a level of hit molecule diversity that is not achievable with any particular single method. We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes. This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective.

Mespeus--a database of metal interactions with proteins.

Modeling and analogy are commonly used to identify the part that a metal may play in the structure or function of a new protein which has been recognized by structural genomics. Mespeus ( http://mespeus.bch.ed.ac.uk/MESPEUS_10/) lists metal protein interactions whose geometry has been experimentally determined and allows them to be visualized. This can contribute to the modeling process. The use of Mespeus is described with a series of examples.

Toward an integrated software platform for systems pharmacology.

Understanding complex biological systems requires the extensive support of computational tools. This is particularly true for systems pharmacology, which aims to understand the action of drugs and their interactions in a systems context. Computational models play an important role as they can be viewed as an explicit representation of biological hypotheses to be tested. A series of software and data resources are used for model development, verification and exploration of the possible behaviors of biological systems using the model that may not be possible or not cost effective by experiments. Software platforms play a dominant role in creativity and productivity support and have transformed many industries, techniques that can be applied to biology as well. Establishing an integrated software platform will be the next important step in the field.

Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology.

Increased availability of bioinformatics resources is creating opportunities for the application of network pharmacology to predict drug effects and toxicity resulting from multi-target interactions. Here we present a high-precision computational prediction approach that combines two elaborately built machine learning systems and multiple molecular docking tools to assess binding potentials of a test compound against proteins involved in a complex molecular network. One of the two machine learning systems is a re-scoring function to evaluate binding modes generated by docking tools. The second is a binding mode selection function to identify the most predictive binding mode. Results from a series of benchmark validations and a case study show that this approach surpasses the prediction reliability of other techniques and that it also identifies either primary or off-targets of kinase inhibitors. Integrating this approach with molecular network maps makes it possible to address drug safety issues by comprehensively investigating network-dependent effects of a drug or drug candidate.

Software for systems biology: from tools to integrated platforms.

Understanding complex biological systems requires extensive support from software tools. Such tools are needed at each step of a systems biology computational workflow, which typically consists of data handling, network inference, deep curation, dynamical simulation and model analysis. In addition, there are now efforts to develop integrated software platforms, so that tools that are used at different stages of the workflow and by different researchers can easily be used together. This Review describes the types of software tools that are required at different stages of systems biology research and the current options that are available for systems biology researchers. We also discuss the challenges and prospects for modelling the effects of genetic changes on physiology and the concept of an integrated platform.

EDULISS: a small-molecule database with data-mining and pharmacophore searching capabilities.

We present the relational database EDULISS (EDinburgh University Ligand Selection System), which stores structural, physicochemical and pharmacophoric properties of small molecules. The database comprises a collection of over 4 million commercially available compounds from 28 different suppliers. A user-friendly web-based interface for EDULISS (available at http://eduliss.bch.ed.ac.uk/) has been established providing a number of data-mining possibilities. For each compound a single 3D conformer is stored along with over 1600 calculated descriptor values (molecular properties). A very efficient method for unique compound recognition, especially for a large scale database, is demonstrated by making use of small subgroups of the descriptors. Many of the shape and distance descriptors are held as pre-calculated bit strings permitting fast and efficient similarity and pharmacophore searches which can be used to identify families of related compounds for biological testing. Two ligand searching applications are given to demonstrate how EDULISS can be used to extract families of molecules with selected structural and biophysical features.

An improved strategy for the crystallization of Leishmania mexicana pyruvate kinase.

The inclusion of novel small molecules in crystallization experiments has provided very encouraging results and this method is now emerging as a promising alternative strategy for crystallizing 'problematic' biological macromolecules. These small molecules have the ability to promote lattice formation through stabilizing intermolecular interactions in protein crystals. Here, the use of 1,3,6,8-pyrenetetrasulfonic acid (PTS), which provides a helpful intermolecular bridge between Leishmania mexicana PYK (LmPYK) macromolecules in the crystal, is reported, resulting in the rapid formation of a more stable crystal lattice at neutral pH and greatly improved X-ray diffraction results. The refined structure of the LmPYK-PTS complex revealed the negatively charged PTS molecule to be stacked between positively charged (surface-exposed) arginine side chains from neighbouring LmPYK molecules in the crystal lattice.