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

UC-426 Cybersecurity Park

We are presenting two additional modules to the Cyber Security Park, a long-running game project that is part of the realities lab. Whack-a-Malware is an arcade game where the player has to whack various malware, each with unique effects that mimic real-world malware. This includes Adware, Spyware, Ransomware, Computer Worms, and Trojan Horses. The player is equipped with two hammers that instantly destroy malware. But it goes on a three-second cooldown every time they destroy something. The player can reduce the cooldown by destroying adware as they are the main cause of slowing down the computer. Digital Footprints Private Investigator is a complete rework of an existing module. The player will be tasked by their client to find the perpetrator who has been anonymously intimidating them online and in person. The Player will have to explore the city to find digital footprint clues that will provide alibis and evidence against the suspects in the case

SuperDRUG2: a one stop resource for approved/marketed drugs

Regular monitoring of drug regulatory agency web sites and similar resources for information on new drug approvals and changes to legal status of marketed drugs is impractical. It requires navigation through several resources to find complete information about a drug as none of the publicly accessible drug databases provide all features essential to complement in silico drug discovery. Here, we propose SuperDRUG2 (http://cheminfo.charite.de/superdrug2) as a comprehensive knowledge-base of approved and marketed drugs. We provide the largest collection of drugs (containing 4587 active pharmaceutical ingredients) which include small molecules, biological products and other drugs. The database is intended to serve as a one-stop resource providing data on: chemical structures, regulatory details, indications, drug targets, side-effects, physicochemical properties, pharmacokinetics and drug-drug interactions. We provide a 3D-superposition feature that facilitates estimation of the fit of a drug in the active site of a target with a known ligand bound to it. Apart from multiple other search options, we introduced pharmacokinetics simulation as a unique feature that allows users to visualise the 'plasma concentration versus time' profile for a given dose of drug with few other adjustable parameters to simulate the kinetics in a healthy individual and poor or extensive metabolisers

Topological Magnons in Kitaev Magnets at High Fields

We study the Kitaev-Heisenberg-$\Gamma$-$\Gamma'$ model that describes the magnetism in strong spin-orbit coupled honeycomb lattice Mott insulators. In strong $[111]$ magnetic fields that bring the system into the fully polarized paramagnetic phase, we find that the spin wave bands carry nontrivial Chern numbers over large regions of the phase diagram implying the presence of chiral magnon edge states. In contrast to other topological magnon systems, the topological nontriviality of these systems results from the presence of magnon number non-conserving terms in the Hamiltonian. Since the effects of interactions are suppressed by $J/h$, the validity of the single particle picture is tunable making paramagnetic phases particularly suitable for the exploration of this physics. Using time dependent DMRG and interacting spin wave theory, we demonstrate the presence of the chiral edge mode and its evolution with field.Comment: 16 pages (main text + supplementary material), 10 figure

Periodic points in random substitution subshifts

We study various aspects of periodic points for random substitution subshifts. In order to do so, we introduce a new property for random substitutions called the disjoint images condition. We provide a procedure for determining the property for compatible random substitutions—random substitutions for which a well-defined abelianisation exists. We find some simple necessary criteria for primitive, compatible random substitutions to admit periodic points in their subshifts. In the case that the random substitution further has disjoint images and is of constant length, we provide a stronger criterion. A method is outlined for enumerating periodic points of any specified length in a random substitution subshift

The receptor tyrosine kinase MerTK regulates dendritic cell production of BAFF

The MerTK receptor tyrosine kinase is an important negative regulator of dendritic cell function and is required to prevent B cell autoimmunity in vivo. It is not currently known however, if any causal relationship exists between these two aspects of MerTK function. We sought to determine if dendritic cells from mice lacking MerTK (mertk−/− mice) have characteristics that may aid in the development of B cell autoimmunity. Specifically, we found that mertk−/− mice contain an elevated number of splenic dendritic cells, and this population contains an elevated proportion of cells secreting the critical B cell pro-survival factor, B cell activating factor (BAFF). Elevated numbers of BAFF-secreting cells were also detected among mertk−/− bone marrow-derived dendritic cell (BMDC) populations. This was observed in both resting BMDC, and BMDC stimulated with lipopolysaccharide (LPS) or treated with exogenous apoptotic cells. We also found that dendritic cells in general have a pro-survival effect on resting B cells in co-culture. However, despite containing more BAFF-secreting cells, mertk−/− BMDC were not superior to C57BL/6 or baff-deficient BMDC at promoting B cell survival. Furthermore, using decoy receptors, we show that dendritic cells may promote B cell survival and autoimmunity through a BAFF-and APRIL-independent mechanism

Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized

Understanding protein structure is of crucial importance in science, medicine and biotechnology. For about two decades, knowledge based potentials based on pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been center stage in the prediction and design of protein structure and the simulation of protein folding. However, the validity, scope and limitations of these potentials are still vigorously debated and disputed, and the optimal choice of the reference state -- a necessary component of these potentials -- is an unsolved problem. PMFs are loosely justified by analogy to the reversible work theorem in statistical physics, or by a statistical argument based on a likelihood function. Both justifications are insightful but leave many questions unanswered. Here, we show for the first time that PMFs can be seen as approximations to quantities that do have a rigorous probabilistic justification: they naturally arise when probability distributions over different features of proteins need to be combined. We call these quantities reference ratio distributions deriving from the application of the reference ratio method. This new view is not only of theoretical relevance, but leads to many insights that are of direct practical use: the reference state is uniquely defined and does not require external physical insights; the approach can be generalized beyond pairwise distances to arbitrary features of protein structure; and it becomes clear for which purposes the use of these quantities is justified. We illustrate these insights with two applications, involving the radius of gyration and hydrogen bonding. In the latter case, we also show how the reference ratio method can be iteratively applied to sculpt an energy funnel. Our results considerably increase the understanding and scope of energy functions derived from known biomolecular structures

Molecular determinants of binding to the Plasmodium subtilisin-like protease 1.

PfSUB1, a subtilisin-like protease of the human malaria parasite Plasmodium falciparum, is known to play important roles during the life cycle of the parasite and has emerged as a promising antimalarial drug target. In order to provide a detailed understanding of the origin of binding determinants of PfSUB1 substrates, we performed molecular dynamics simulations in combination with MM-GBSA free energy calculations using a homology model of PfSUB1 in complex with different substrate peptides. Key interactions, as well as residues that potentially make a major contribution to the binding free energy, are identified at the prime and nonprime side of the scissile bond and comprise peptide residues P4 to P2'. This finding stresses the requirement for peptide substrates to interact with both prime and nonprime side residues of the PfSUB1 binding site. Analyzing the energetic contributions of individual amino acids within the peptide-PfSUB1 complexes indicated that van der Waals interactions and the nonpolar part of solvation energy dictate the binding strength of the peptides and that the most favorable interactions are formed by peptide residues P4 and P1. Hot spot residues identified in PfSUB1 are dispersed over the entire binding site, but clustered areas of hot spots also exist and suggest that either the S4-S2 or the S1-S2' binding site should be exploited in efforts to design small molecule inhibitors. The results are discussed with respect to which binding determinants are specific to PfSUB1 and, therefore, might allow binding selectivity to be obtained

CSAR Benchmark Exercise of 2010: Selection of the Protein–Ligand Complexes

ABSTRACT: A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) aims to collect available data from industry and academia which may be used for this purpose (www.csardock.org). Also, CSAR is charged with organizing community-wide exercises based on the collected data. The first of these exercises was aimed to gauge the overall state of docking and scoring, using a large and diverse data set of protein ligand complexes. Participants were asked to calculate the affinity of the complexes as provided and then recalculate with changes which may improve their specific method. This first data set was selected from existing PDB entries which had binding data (Kd or Ki) in Binding MOAD, augmented with entries from PDBbind. The final data set contains 343 diverse protein ligand complexes and spans 14 pKd. Sixteen proteins have three or more complexes in the data set, from which a user could start an inspection of congeneric series. Inherent experimental error limits the possible correlation between scores and measured affinity; R 2 is limited to ∼0.9 when fitting to the data set without over parametrizing. R 2 is limited to ∼0.8 when scoring the data set with a method trained on outside data. The details of how the data set was initially selected, and the process by which it matured t