Two Methods,One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses

In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein–ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Particularly for flexible proteins, such as kinases, and larger ligands cocrystallization captures more reliable the correct binding pose and induced protein adaptations. The geometrical discrepancies between soaking and cocrystallization appear smaller for fragment-sized ligands. For larger flexible ligands that trigger conformational changes of the protein, soaking can be misleading and underestimates the number of possible polar interactions due to inadequate, highly impaired positions of protein amino-acid side and main chain atoms. Thus, if applicable cocrystallization should be the gold standard to study protein–ligand complexes.     

Chemoenzymatic Total Synthesis of Sorbicatechol Structural Analogues and Evaluation of Their Antiviral Potential

Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatechol A, which is reported to have antiviral activity, particularly against influenza A virus (H1N1). Through a straightforward, one-pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2-methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.     

Investigation of the influence of iron-containing abrasives on the corrosion behaviour of the aluminium alloy AlSi1.2Mg0.4

The corrosion resistance of aluminium surfaces is closely linked to the surface state after a grinding process. For years, iron-containing abrasive materials were suspected to lead to increased corrosion susceptibility after processing of aluminium surfaces. To prove a possible correlation between the iron content of an abrasive and the corrosion behaviour of aluminium components, scientific investigations and experimentally practical corrosion tests are necessary. For the current investigation, specimens of a technical Al-Si alloy from the same batch were used. The test specimens were mechanically ground with various resin-bonded model abrasives containing different iron contents. The performed corrosion tests did not reveal a negative influence of the different iron-containing abrasives on the corrosion behaviour of the Al–Si alloy. However, the most sensitive measuring method (electrochemical noise) showed differences in the surface activity depending on the type of abrasive.     

A concise nodal-based derivation of the floating frame of reference formulation for displacement-based solid finite elements

Multibody System Dynamics - The Floating Frame of Reference Formulation (FFRF) is one of the most widely used methods to analyze flexible multibody systems subjected to large rigid-body motion but...     

Self-report measures for the assessment of human–machine interfaces in automated driving

Cognition, Technology & Work - For a successful market introduction of Level 3 Automated Driving Systems (L3 ADS), a careful evaluation of human–machine interfaces (HMIs) is necessary....     

Deep and narrow impact: introducing location filtered citation counting

Scientometrics - The present study tests a citation counting method that filters out citations in the introductory and backgrounds sections and then weighs the remaining citations by their in-text...     

Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.     

Properties and microstructure of copper-alloyed solid solution-strengthened ductile iron

Solid solution-strengthened ductile iron (DI) exhibits outstanding mechanical properties due to the high silicon content. The strengthening by silicon addition is limited since additions above 4.3?wt-% lead to embrittlement. For a further improvement of mechanical properties, other alloying elements need to be considered. In the present work, the effect of various copper additions on the microstructure and the mechanical properties of solid solution-strengthened DI were investigated. The results show that no appreciable strengthening can be achieved by copper addition without the formation of pearlite in the matrix. The pearlite content increases considerably for Cu-additions above 0.23?wt-% and is independent of the cooling rate for the cooling conditions analysed.     

Solvent-Free Plasticity and Programmable Mechanical Behaviors of Engineered Proteins

Biopolymeric networks with plasticity show great competences in diverse fields owing to the combined biocompatible and mechanical characteristics. However, to realize such plasticity external complicated treatments, e.g., UV or organic solvent have to be applied, which in turn impair the biological nature and even mechanical properties of those systems. To address this challenge, one new type of anhydrous protein liquid crystalline (LC) gels, which exhibit flexible morphological plasticity and mechanical programmability is demonstrated. Supramolecular interactions in the smectic biogels play an important role for their high plasticity. Remarkably, the samples exhibit outstanding mechanical behaviors. The tensile strength and Young's modulus at MPa levels are comparable or even higher than chemically cross-linked hydrogels and LC elastomers. More importantly, mechanical programmability of the LC gels is achieved by genetically tuning the charge density of protein backbones. Consequently, the mechanical performance is manipulated in the range of one order of magnitude. Thus, this type of anhydrous protein LC gels offers great opportunities for load-bearing high-tech applications.