Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

In situ assembled ZIF superstructures via an emulsion-free soft-templating approach

Assembling well-defined MOF superstructures remains challenging as it requires easily removable hard templates or readily available immiscible solutions for an emulsion-based soft-template approach. In this work, a single-step emulsion-free soft templating approach is reported to spontaneously prepare hollow ZIF-8 and ZIF-67 colloidosomes with no further purification. These superstructures can load different enzymes regardless of the size and charge with a high encapsulation efficiency of 99%. We envisage that this work will expand the repertoires of MOF superstructures by the judicious selection of precursors and the reaction medium.

An emulsion-free approach for the preparation of hollow ZIF-8 superstructures in a single step is established based on metal sulfate hydrates in methanol.     

Note sur le mécanisme réactionnel de la transposition de Dimroth. Une étude ab initio

An ab initio study of the Dimorth rerarrangement of the -amino-1,2,3,4-tetrazole leads to the conclusion teht in vapour phase the rate determining step is not the ring-chain isomerism, but is either the Z-E iomerism around the C?N double bond or the 1,3-sigmatropic shift of the proton.     

New dinuclear catalysts Rh(2)(N-O)(2)[(C6H4)P(C6H5)2]2 with imidate ligands: synthesis and isomerization from head-to-tail to head-to-head configuration of the imidate ligands

Two new dirhodium(II) catalysts of general formula Rh(2)(N-O)(2)[(C(6)H(4))P(C(6)H(5))(2)](2) (N-O = C(4)H(4)NO(2)) are prepared, starting from Rh(2)(O(2)CCH(3))(2)(PC)(2)L(2) [PC = (C(6)H(4))P(C(6)H(5))(2) (head-to-tail arrangement); L = HO(2)CCH(3)]. The thermal reaction of Rh(2)(O(2)CCH(3))(2)(PC)(2).L(2) with the neutral succinimide stereoselectively gives one compound that according to the X-ray structure determination has the formula Rh(2)(C(4)H(4)NO(2))(2)[(C(6)H(4))P(C(6)H(5))(2)](2) (1). It corresponds to the polar isomer with two bridging imidate ligands in a head-to-head configuration. However, stepwise reaction of Rh(2)(O(2)CCH(3))(2)(PC)(2).L(2) with (CH(3))(3)SiCl and potassium succinimidate yields a mixture of 1 and one of the two possible isomers (structure B) with a head-to-tail configuration of the imidate ligands, Rh(2)(C(4)H(4)NO(2))(2)[(C(6)H(4))P(C(6)H(5))(2)](2) (2), also characterized by X-ray methods. In solution, compound 2 undergoes slow isomerization to 1; the rate of this process is enhanced by the presence of acetonitrile. Compounds 1 and 2 are obtained as pure enantiomers starting from (M)- and (P)-Rh(2)(O(2)CCH(3))(2)(PC)(2).L(2) rather than from the racemic mixture. Their enantioselectivities in cyclopropanation of 1-diazo-5-penten-2-one are similar to those reported for the dirhodium amidate catalysts.     

The synthesis and physical evaluation of 5-alkoxy-1,3-thiazoles prepared via Lawesson's reagent-mediated cyclisation of α-benzamido esters

The synthesis of the first series of 5-alkoxy-1,3-thiazole-based liquid crystals is reported. The aforementioned liquid crystals were synthesised through a Lawesson's reagent-mediated cyclisation of appropriate α-benzamido esters. This methodology was found to be highly efficient, even on a large scale, and the resulting 5-alkoxy-1,3-thiazoles could be purified without the use of column chromatography. The synthesis and mesomorphic properties of a family of 5-alkoxy-2-(4-cyanophenyl)-1,3-thiazole liquid crystals prepared via this approach are discussed and compared with their thiophene and phenyl analogues.     

Brief survey on phytochemicals to prevent COVID-19

BackgroundThe recent pandemic by COVID-19 is a global threat to human health. The disease is caused by SARS-CoV-2 and the infection rate is increased more quickly than MERS and SARS as their rapid adaptation to varied climatic conditions through rapid mutations. It becomes more severe due to the lack of proper therapeutic drugs, insufficient diagnostic tool, scarcity of appropriate drug, life supporting medical facility and mostly lack of awareness. Therefore, preventive measure is one of the important strategies to control. In this context, herbal medicinal plants received a noticeable attention to treat COVID-19 in Indian subcontinent. Here, 44 Indian traditional plants have been discussed with their novel phytochemicals that prevent the novel corona virus. The basic of SARS-CoV-2, their common way of transmission including their effect on immune and nervous system have been discussed. We have analysed their mechanism of action against COVID-19 following in-silico analysis. Their probable mechanism and therapeutic approaches behind the activity of phytochemicals to stimulate immune response as well as inhibition of viral multiplication discussed rationally. Thus, mixtures of active secondary metabolites/phytochemicals are the only choice to prevent the disease in countries where vaccination will take long time due to overcrowded population density.     

Pullulan Encapsulation of Labile Biomolecules to Give Stable Bioassay Tablets

A simple and inexpensive method is reported for the long‐term stabilization of enzymes and other unstable reagents in premeasured quantities in water‐soluble tablets (cast, not compressed) made with pullulan, a nonionic polysaccharide that forms an oxygen impermeable solid upon drying. The pullulan tablets dissolve in aqueous solutions in seconds, thereby facilitating the easy execution of bioassays at remote sites with no need for special reagent handling and liquid pipetting. This approach is modular in nature, thus allowing the creation of individual tablets for enzymes and their substrates. Proof‐of‐principle demonstrations include a Taq polymerase tablet for DNA amplification through PCR and a pesticide assay kit consisting of separate tablets for acetylcholinesterase and its chromogenic substrate, indoxyl acetate, both of which are highly unstable. The encapsulated reagents remain stable at room temperature for months, thus enabling the room‐temperature shipping and storage of bioassay components.