SuperCYPsPred - a web server for the prediction of cytochrome activity

Cytochrome P450 enzymes (CYPs)-mediated drug metabolism influences drug pharmacokinetics and results in adverse outcomes in patients through drug-drug interactions (DDIs). Absorption, distribution, metabolism, excretion and toxicity (ADMET) issues are the leading causes for the failure of a drug in the clinical trials. As details on their metabolism are known for just half of the approved drugs, a tool for reliable prediction of CYPs specificity is needed. The SuperCYPsPred web server is currently focused on five major CYPs isoenzymes, which includes CYP1A2, CYP2C19, CYP2D6, CYP2C9 and CYP3A4 that are responsible for more than 80% of the metabolism of clinical drugs. The prediction models for classification of the CYPs inhibition are based on well-established machine learning methods. The models were validated both on cross-validation and external validation sets and achieved good performance. The web server takes a 2D chemical structure as input and reports the CYP inhibition profile of the chemical for 10 models using different molecular fingerprints, along with confidence scores, similar compounds, known CYPs information of drugs-published in literature, detailed interaction profile of individual cytochromes including a DDIs table and an overall CYPs prediction radar chart (http://insilico-cyp.charite.de/SuperCYPsPred/).The web server does not require log in or registration and is free to use

Stationarity, soft ergodicity, and entropy in relativistic systems

Recent molecular dynamics simulations show that a dilute relativistic gas equilibrates to a Juettner velocity distribution if ensemble velocities are measured simultaneously in the observer frame. The analysis of relativistic Brownian motion processes, on the other hand, implies that stationary one-particle distributions can differ depending on the underlying time-parameterizations. Using molecular dynamics simulations, we demonstrate how this relativistic phenomenon can be understood within a deterministic model system. We show that, depending on the time-parameterization, one can distinguish different types of soft ergodicity on the level of the one-particle distributions. Our analysis further reveals a close connection between time parameters and entropy in special relativity. A combination of different time-parameterizations can potentially be useful in simulations that combine molecular dynamics algorithms with randomized particle creation, annihilation, or decay processes.Comment: 4 page

Derivatives of spin dynamics simulations

We report analytical equations for the derivatives of spin dynamics simulations with respect to pulse sequence and spin system parameters. The methods described are significantly faster, more accurate and more reliable than the finite difference approximations typically employed. The resulting derivatives may be used in fitting, optimization, performance evaluation and stability analysis of spin dynamics simulations and experiments. Keywords: NMR, EPR, simulation, analytical derivatives, optimal control, spin chemistry, radical pair.Comment: Accepted by The Journal of Chemical Physic

mVOC: a database of microbial volatiles

Scents are well known to be emitted from flowers and animals. In nature, these volatiles are responsible for inter- and intra-organismic communication, e.g. attraction and defence. Consequently, they influence and improve the establishment of organisms and populations in ecological niches by acting as single compounds or in mixtures. Despite the known wealth of volatile organic compounds (VOCs) from species of the plant and animal kingdom, in the past, less attention has been focused on volatiles of microorganisms. Although fast and affordable sequencing methods facilitate the detection of microbial diseases, however, the analysis of signature or fingerprint volatiles will be faster and easier. Microbial VOCs (mVOCs) are presently used as marker to detect human diseases, food spoilage or moulds in houses. Furthermore, mVOCs exhibited antagonistic potential against pathogens in vitro, but their biological roles in the ecosystems remain to be investigated. Information on volatile emission from bacteria and fungi is presently scattered in the literature, and no public and up-to-date collection on mVOCs is available. To address this need, we have developed mVOC, a database available online at http://bioinformatics.charite.de/mvoc

The Simple Non-degenerate Relativistic Gas: Statistical Properties and Brownian Motion

This paper shows a novel calculation of the mean square displacement of a classical Brownian particle in a relativistic thermal bath. The result is compared with the expressions obtained by other authors. Also, the thermodynamic properties of a non-degenerate simple relativistic gas are reviewed in terms of a treatment performed in velocity space.Comment: 6 pages, 2 figure

The Transformer database: biotransformation of xenobiotics

As the number of prescribed drugs is constantly rising, drug-drug interactions are an important issue. The simultaneous administration of several drugs can cause severe adverse effects based on interactions with the same metabolizing enzyme(s). The Transformer database (http://bioinformatics.charite.de/transformer) contains integrated information on the three phases of biotransformation (modification, conjugation and excretion) of 3000 drugs and >350 relevant food ingredients (e.g. grapefruit juice) and herbs, which are catalyzed by 400 proteins. A total of 100 000 interactions were found through text mining and manual validation. The 3D structures of 200 relevant proteins are included. The database enables users to search for drugs with a visual display of known interactions with phase I (Cytochrome P450) and phase II enzymes, transporters, food and herbs. For each interaction, PubMed references are given. To detect mutual impairments of drugs, the drug-cocktail tool displays interactions between selected drugs. By choosing the indication for a drug, the tool offers suggestions for alternative medications to avoid metabolic conflicts. Drug interactions can also be visualized in an interactive network view. Additionally, prodrugs, including their mechanisms of activation, and further information on enzymes of biotransformation, including 3D models, can be viewed

Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy

The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen

Super natural II -a database of natural products

Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ∼ 50,000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ∼ 326,000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ∼ 170,000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins

Enhanced Antibody Production in Clever-1/Stabilin-1-Deficient Mice

Clever-1, encoded by the Stab1 gene, is a scavenger and leukocyte trafficking receptor expressed by subsets of vascular and lymphatic endothelial cells and immunosuppressive macrophages. Monocyte Clever-1 also modulates T cell activation. However, nothing is known about the possible links between B cell function and Clever-1. Here, we found that Stab1 knockout mice (Stab1(-/-)) lacking the Clever-1 protein from all cells present with abnormally high antibody levels under resting conditions and show enhanced humoral immune responses after immunization with protein and carbohydrate antigens. Removal of the spleen does not abolish the augmented basal and post-immunization antibody levels in Clever-1-deficient mice. The increased IgG production is also present in mice in which Clever-1 is selectively ablated from macrophages. When compared to wildtype macrophages, Clever-1-deficient macrophages show increased TNF-alpha synthesis. In co-culture experiments, monocytes/macrophages deficient of Clever-1 support higher IgM production by B cells, which is blocked by TNF-alpha depletion. Collectively, our data show that the excessive inflammatory activity of monocytes/macrophages in the absence of Clever-1 results in augmented humoral immune responses in vivo

Relative entropy, Haar measures and relativistic canonical velocity distributions

The thermodynamic maximum principle for the Boltzmann-Gibbs-Shannon (BGS) entropy is reconsidered by combining elements from group and measure theory. Our analysis starts by noting that the BGS entropy is a special case of relative entropy. The latter characterizes probability distributions with respect to a pre-specified reference measure. To identify the canonical BGS entropy with a relative entropy is appealing for two reasons: (i) the maximum entropy principle assumes a coordinate invariant form; (ii) thermodynamic equilibrium distributions, which are obtained as solutions of the maximum entropy problem, may be characterized in terms of the transformation properties of the underlying reference measure (e.g., invariance under group transformations). As examples, we analyze two frequently considered candidates for the one-particle equilibrium velocity distribution of an ideal gas of relativistic particles. It becomes evident that the standard J\"uttner distribution is related to the (additive) translation group on momentum space. Alternatively, imposing Lorentz invariance of the reference measure leads to a so-called modified J\"uttner function, which differs from the standard J\"uttner distribution by a prefactor, proportional to the inverse particle energy.Comment: 15 pages: extended version, references adde