Harnessing Protein-Ligand Interaction Fingerprints to Predict New Scaffolds of RIPK1 Inhibitors

Necroptosis has emerged as an exciting target in oncological, inflammatory, neurodegenerative, and autoimmune diseases, in addition to acute ischemic injuries. It is known to play a role in innate immune response, as well as in antiviral cellular response. Here we devised a concerted in silico and experimental framework to identify novel RIPK1 inhibitors, a key necroptosis factor. We propose the first in silico model for the prediction of new RIPK1 inhibitor scaffolds by combining docking and machine learning methodologies. Through the data analysis of patterns in docking results, we derived two rules, where rule #1 consisted of a four-residue signature filter, and rule #2 consisted of a six-residue similarity filter based on docking calculations. These were used in consensus with a machine learning QSAR model from data collated from ChEMBL, the literature, in patents, and from PubChem data. The models allowed for good prediction of actives of >90, 92, and 96.4% precision, respectively. As a proof-of-concept, we selected 50 compounds from the ChemBridge database, using a consensus of both molecular docking and machine learning methods, and tested them in a phenotypic necroptosis assay and a biochemical RIPK1 inhibition assay. A total of 7 of the 47 tested compounds demonstrated around 20–25% inhibition of RIPK1’s kinase activity but, more importantly, these compounds were discovered to occupy new areas of chemical space. Although no strong actives were found, they could be candidates for further optimization, particularly because they have new scaffolds. In conclusion, this screening method may prove valuable for future screening efforts as it allows for the exploration of new areas of the chemical space in a very fast and inexpensive manner, therefore providing efficient starting points amenable to further hit-optimization campaigns.     

Pulsed Nd:YAG laser welding of AISI 304 to AISI 420 stainless steels

The technique to weld AISI 304 stainless steel to AISI 420 stainless steel with a pulsed Nd:YAG laser has been investigated. The main objective of this study was to determine the influence of the laser beam position, with respect to the joint, on weld characteristics. Specimens were welded with the laser beam incident on the joint and moved 0.1 and 0.2 mm on either side of the joint. The joints were examined in an optical microscope for cracks, pores and to determine the weld geometry. The microstructure of the weld and the heat affected zones were observed in a scanning electron microscope. An energy dispersive spectrometer, coupled to the scanning electron microscope, was used to determine variations in (weight %) the main chemical elements across the fillet weld. Vickers microhardness testing and tensile testing were carried out to determine the mechanical properties of the weld. The results of the various tests and examinations enabled definition of the best position for the incident laser beam with respect to the joint, for welding together the two stainless steels.     

New organocatalysts derived from tartaric and glyceric acids for direct aldol reactions

The synthesis of several new pyrrolidine based asymmetric organocatalysts derived from tartaric, glyceric acids and a pyrrolidine moiety is described with a study of their application in the development of an enantioselective aldol protocol. The influence of different proton donor groups, such as a primary hydroxyl or a carboxylic acid group, or their absence, on the efficiency of the organocatalyst was studied. The configuration of the tartrate derived catalysts and the presence of the rigid butane-2,3-diacetal were found to have a strong influence on the stereoselective outcome of the aldol reaction.     

Laser stabilization to an atomic transition using an optically generated dispersive line shape

We report a simple and robust technique to generate a dispersive signal which serves as an error signal to electronically stabilize a monomode continuous-wave laser emitting around an atomic resonance. We explore nonlinear effects in the laser beam propagation through a resonant vapor by way of spatial filtering. The performance of this technique is validated by locking semiconductor lasers to the cesium and rubidium D₂ lines and observing long-term reduction of the emission frequency drifts, making the lasers well adapted for many atomic physics applications.     

Propargylation of aromatic compounds using Ce(OTf)3 as catalyst

Ce(OTf)₃ was successfully employed as catalyst for the activation of the hydroxyl group in the Friedel–Crafts reaction of aromatic compounds with propargylic alcohols in nitromethane. The products were obtained in good to excellent yields.     

Stability constants of metal complexes of macrocyclic ligands with pendant donor groups

Abstract

In our studies of the stability constants of metal complexes, we have investigated a number of macrocyclic ligands with pendant donor groups. The ligands are characterized by the fact that they have nitrogen donors in the macrocyclic ring and oxygen or sulfur donors in the pendant arms. These ligands represent seven different macrocycles, and by varying the pendant donor groups, ten different ligands are indicated. The affinities of these ligands for fifteen metal ions will be described. The Fe(III) complex of triazanonane with o-hydroxypyridyl or o-hydroxybenzyl pendant donor groups are the most stable ferric complexes ever reported. The In(III) complex of triazacyclononane with pendant mercaptoethyl donor groups, is exceptionally stable. Also, the Ca(II) complex of DOTA probably has the highest stability of any calcium(II) complex. These, and other comparisons will be made on the basis of the thermodynamic stability constant data for the ligands described.