Voltage-gated sodium channels: structures, functions, and molecular modeling

Recent developments in next generation (S)-proline-derived chiral organocatalysts

Nitroaromatic compounds (NACs) are ubiquitous in the environment due to their extensive industrial applications. The recalcitrance of NACs causes their arduous degradation, subsequently bringing about potential threats to human health and environmental safety. The problem of how to effectively predict the toxicity of NACs has drawn public concern over time. Quantitative structure–activity relationship (QSAR) is introduced as a cost-effective tool to quantitatively predict the toxicity of toxicants. Both OECD (Organization for Economic Co-operation and Development) and REACH (Registration, Evaluation and Authorization of Chemicals) legislation have promoted the use of QSAR as it can significantly reduce living animal testing. Although numerous QSAR studies have been conducted to evaluate the toxicity of NACs, systematic reviews related to the QSAR modeling of NACs toxicity are less reported. The purpose of this review is to provide a thorough summary of recent QSAR studies on the toxic effects of NACs according to the corresponding classes of toxic response endpoints.

Quantitative Structure-Activity Relationship (QSAR) Studies on the Toxic Effects of Nitroaromatic Compounds (NACs): A Systematic Review.

Comparative toxicity of multiple exposure routes of pyraclostrobin in adult zebrafish (Danio rerio).

Quantum chemical descriptors in quantitative structure–activity relationship models and their applications

Quantitative structure-toxicity relationship model for acute toxicity of organophosphates via multiple administration routes in rats and mice

Design and Synthesis of L‐Proline Derivatives as Enantioselective Organocatalysts for Synthesis of the (S)‐Wieland‐Miescher Ketone

Nav 1.2, a member of voltage-gated sodium channels (Nav s) that are responsible for the generation and propagation of action potentials along the cell membrane, and play a vital role in the process of information transmission within the nervous system and muscle contraction, is preferentially expressed in the central nervous system. As a potent and selective blocker of Nav s, tetrodotoxin (TTX) has been extensively studied in biological and chemical sciences, whereas the detailed mechanism by which it blocks nine Nav 1 channel subtypes remain elusive. Despite the high structural similarity, the TTX metabolite 4,9-anhydro-TTX is 161 times less effective toward the mammalian Nav 1.2, which puzzled us to ask a question why such a subtle structural variation results in the largely binding affinity difference. In the current work, an integrated computational strategy, including homology modeling, induced fit docking, explicit-solvent MD simulations, and free energy calculations, was employed to investigate the binding mechanism and conformational determinants of TTX analogs. Based on the computational results, the H-bond interactions between C4-OH and C9-OH of TTX and the outer ring carboxylates of the selectivity-filter residues, and the cation-π interaction between the primary amine of guanidinium of TTX and Phe385 determine the difference of their binding affinities. Moreover, the computationally simulations were carried out for the D384N and E945K mutants of hNav 1.2-TTX, and the rank of the predicted binding free energies is in accordance with the experimental data. These observations provide a valuable model to design potent and selective neurotoxins of Nav 1.2 and shed light on the blocking mechanism of TTX to sodium channels.

Insight into tetrodotoxin blockade and resistance mechanisms of Nav1.2 sodium channel by theoretical approaches

The invention relates to a preparation method of (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone. According to the preparation method, an L-proline derivative is used as a chiral catalyst and microwave radiation is introduced into chiral preparation of the (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone for the first time through asymmetric Robinson cyclization reaction under conventional conditions or microwave irradiation conditions. Under proper power, an L-prolinamide type catalyst can keep excellent catalysis performance and the catalysis reaction time isshortened; compared with room-temperature stirring conditions, the synthesis efficiency is greatly improved. The molecular collision is aggravated through the microwave radiation and an intermediatecan more easily pass through an energy barrier to form a transition state, so that the reaction time is remarkably shortened, the preparation efficiency of the (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone is greatly improved and the synthesis period is shortened. The method is low in cost, simple and rapid, high in yield and good in stereoselectivity.

Junjie Ding

Papers

Quantitative structure-toxicity relationship model for acute toxicity of organophosphates via multiple administration routes in rats and mice

Design and Synthesis of L‐Proline Derivatives as Enantioselective Organocatalysts for Synthesis of the (S)‐Wieland‐Miescher Ketone

Insight into tetrodotoxin blockade and resistance mechanisms of Nav1.2 sodium channel by theoretical approaches

Preparation method of (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone