Computational Strategies for Broad Spectrum Venom Phospholipase A Inhibitors.

Snakebite envenoming is a persistent cause of mortality and morbidity worldwide due to the logistical challenges and costs of current antibody-based treatments. Their persistence motivates a broad interest in the discovery of inhibitors against multispecies venom phospholipase A (PLA), which are underway as an alternative or supplemental treatment to improve health outcomes. Here, we present new computational strategies for improved inhibitor classification for challenging metalloenzyme targets across many species, including both a new method to utilize existing molecular docking, and subsequent data normalization.

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors.

Background: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity.

PdML (for = 6, 8, 12) nanospheres by post-assembly modification of PdL spheres.

In this contribution, we describe a post-assembly modification approach to selectively coordinate transition metals in PdL cuboctahedra. The herein reported approach involves the preparation of PdL nanospheres with protonated nitrogen donor ligands that are covalently linked at the interior. The so obtained Pd(LH) nanospheres are shown to be suitable for coordinative post-modification after deprotection by deprotonation.

Selective thiazoline peptide cyclisation compatible with mRNA display and efficient synthesis.

Peptide display technologies are a powerful method for discovery of new bioactive sequences, but linear sequences are often very unstable in a biological setting. Macrocyclisation of such peptides is beneficial for target affinity, selectivity, stability, and cell permeability. However, macrocyclisation of a linear hit is unreliable and requires extensive structural knowledge.

biodistribution of kinetically stable PtL nanospheres that show anti-cancer activity.

There is an increasing interest in the application of metal-organic cages (MOCs) in a biomedicinal context, as they can offer non-classical distribution in organisms compared to molecular substrates, while revealing novel cytotoxicity mechanisms. Unfortunately, many MOCs are not sufficiently stable under conditions, making it difficult to study their structure-activity relationships in living cells. As such, it is currently unclear whether MOC cytotoxicity stems from supramolecular features or their decomposition products.

A substrate descriptor based approach for the prediction and understanding of the regioselectivity in caged catalyzed hydroformylation.

The use of data driven tools to predict the selectivity of homogeneous catalysts has received considerable attention in the past years. In these studies often the catalyst structure is varied, but the use of substrate descriptors to rationalize the catalytic outcome is relatively unexplored. To study whether this may be an effective tool, we investigated both an encapsulated and a non-encapsulated rhodium based catalyst in the hydroformylation reaction of 41 terminal alkenes.

Exposing Mechanisms for Defect Clearance in Supramolecular Self-Assembly: Palladium-Pyridine Coordination Revisited.

Spherical three-dimensional (3D) cages composed of palladium(II) and pyridyl ligands are a mainstay of supramolecular chemistry with demonstrated catalytic and optoelectronic applications. The widely reported self-assembly of these palladium-based cages exhibits sensitivity to the solvents, reagents, and/or reactants employed. This sensitivity, and the resulting inconsistency between synthetic protocols, hinders the development of desirable palladium-based cages.

Effector Regulated Catalytic Cyclization of Alkynoic Acids Using Pt L Cages.

Metabolic pathways are highly regulated by effector molecules that influences the rate of enzymatic reactions. Inspired by the catalytic regulation found in living cells, we report a Pt L cage of which the activity can be controlled by effectors that bind inside the cage. The cage shows catalytic activity in the lactonization of alkynoic acids, with the reaction rates dependent on the effector guest bound in the cage.

An Efficient, Site-Selective and Spontaneous Peptide Macrocyclisation During in vitro Translation.

Macrocyclisation provides a means of stabilising the conformation of peptides, often resulting in improved stability, selectivity, affinity, and cell permeability. In this work, a new approach to peptide macrocyclisation is reported, using a cyanobenzothiazole-containing amino acid that can be incorporated into peptides by both in vitro translation and solid phase peptide synthesis, meaning it should be applicable to peptide discovery by mRNA display. This cyclisation proceeds rapidly, with minimal by-products, is selective over other amino acids including non N-terminal cysteines, and is compatible with further peptide elaboration exploiting such an additional cysteine in bicyclisation and derivatisation reactions.

ML Nanospheres with Multiple C Binding Sites for O Formation in Organic and Aqueous Media.

Singlet oxygen is a potent oxidant with major applications in organic synthesis and medicinal treatment. An efficient way to produce singlet oxygen is the photochemical generation by fullerenes which exhibit ideal thermal and photochemical stability. In this contribution we describe readily accessible ML nanospheres with unique binding sites for fullerenes located at the windows of the nanospheres.

Just Add Water: Modulating the Structure-Derived Acidity of Catalytic Hexameric Resorcinarene Capsules.

The hexameric undecyl-resorcin[4]arene capsule () features eight discrete structural water molecules located at the vertices of its cubic suprastructure. Combining NMR spectroscopy with classical molecular dynamics (MD), we identified and characterized two distinct species of this capsule, - and -, respectively featuring 8 and 15 water molecules incorporated into their respective hydrogen-bonded networks. Furthermore, we found that the ratio of the - and - found in solution can be modulated by controlling the water content of the sample.

How to Prepare Kinetically Stable Self-assembled Pt L Nanocages while Circumventing Kinetic Traps.

Supramolecular coordination-based self-assembled nanostructures have been widely studied, and currently various applications are being explored. For several applications, the stability of the nanostructure is of key importance, and this strongly depends on the metal used in the self-assembly process. Herein, design strategies and synthetic protocols to access desirable kinetically stable Pt L nanospheres are reported, and it is demonstrated that these are stable under conditions under which the palladium counterparts decompose.

Topological prediction of palladium coordination cages.

The preparation of functionalized, heteroleptic Pd L coordination cages is desirable for catalytic and optoelectronic applications. Current rational design of these cages uses the angle between metal-binding (∠) sites of the di(pyridyl)arene linker to predict the topology of homoleptic cages obtained non-covalent chemistry. However, this model neglects the contributions of steric bulk between the pyridyl residues-a prerequisite for endohedrally functionalized cages, and fails to rationalize heteroleptic cages.

Balancing Ligand Flexibility versus Rigidity for the Stepwise Self-Assembly of M L via M L Metal-Organic Cages.

Non-covalent interactions are important for directing protein folding across multiple intermediates and can even provide access to multiple stable structures with different properties and functions. Herein, we describe an approach for mimicking this behavior in the self-assembly of metal-organic cages. Two ligands, the bend angles of which are controlled by non-covalent interactions and one ligand lacking the above-mentioned interactions, were synthesized and used for self-assembly with Pd .