ELECTROPHILIC ORGANOSELENIUM COMPOUNDS AND SARS-COV-2: PRO-OXIDANT ACTIVITY AS A MORE PROMISING WAY TOWARDS THE DRUGGABILITY

2021 ◽  
Author(s):  
Claudio Santi ◽  
◽  
Luca Sancineto ◽  
Francesca Mangiavacchi ◽  
Cecilia Scimmi ◽  
...  
Keyword(s):  
Medicinal Chemistry ◽  
General Mechanism ◽  
Organoselenium Compounds ◽  
Covalent Inhibition ◽  
Main Protease ◽  
Promising Application

Ebselent has been recently reported as the most efficient hinibitors of Sars-Cov-2 main protease (Mpro) thought the electrophilic covalent pro-oxidation of the reactive Cysteine 145. According to similar evidences in literature we can propose a general mechanism to explore a novel and promising application of mild organoselenium centered electrophiles in medicinal chemistry. New insights in the field of covalent and non-covalent inhibition of Mpro as well as the antiviral SARS-Cov2 activity of novel organoselenium compounds will be here discussed

scholarly journals Supercomputer simulation of the covalent inhibition of the main protease of SARS-CoV-2

2021 ◽  
Vol 70 (11) ◽  
pp. 2084-2089
Author(s):  
A. V. Nemukhin ◽  
B. L. Grigorenko ◽  
S. V. Lushchekina ◽  
S. D. Varfolomeev
Keyword(s):  
Covalent Inhibition ◽  
Main Protease

scholarly journals Mechanism of inhibition of SARS-CoV-2 Mpro by N3 peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity

2021 ◽  
Author(s):  
Kemel Arafet ◽  
Natalia Serrano-Aparicio ◽  
Alessio Lodola ◽  
Adrian J. Mulholland ◽  
Florenci V. González ◽  
...  
Keyword(s):  
Chemical Reactivity ◽  
Covalent Inhibition ◽  
Mechanism Of Inhibition ◽  
Main Protease ◽  
Mechanism Of Reaction ◽  
Michael Acceptor

QM/MM simulations identify the mechanism of reaction of N3, a covalent peptidyl inhibitor of SARS-CoV-2 main protease. Modelling of two novel proposed compounds, B1 and B2, suggests that reversibility of covalent inhibition could be tailored.

scholarly journals Insights into the Binding and Covalent Inhibition Mechanism of PF-07321332 to SARS-CoV-2 Mpro

2021 ◽  
Author(s):  
Son Tung Ngo ◽  
Trung Hai Nguyen ◽  
Nguyen Thanh Tung ◽  
Binh Khanh Mai
Keyword(s):  
Ligand Binding ◽  
Bound State ◽  
Catalytic Triad ◽  
Inhibition Mechanism ◽  
Binding Process ◽  
Covalent Inhibition ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Covalent Inhibitor

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the COVID-19 pandemic resulting in several million death were reported. Numerous investigations have been carried out to discover a compound that can inhibit the biological activity of SARS-CoV-2 main protease, which is an enzyme related to the viral replication. Among these, PF-07321332 is currently under clinical trial for COVID-19 therapy. Therefore, in this work, atomistic and electronic simulations were performed to unravel the binding and covalent inhibition mechanism of the compound to Mpro. Initially, 5 µs of steered-molecular dynamics simulations were carried out to evaluate the ligand-binding process to SARS-CoV-2 Mpro. Successfully generated bound state between two molecules showed the important role of the PF-07321332 pyrrolidinyl group and the residues Glu166 and Gln189 in the ligand-binding process. Moreover, from the MD-refined structure, quantum mechanics/molecular mechanics (QM/MM) calculations were carried out to unravel the reaction mechanism for the formation of thioimidate product from SARS-CoV-2 Mpro and PF07321332 inhibitor. We found that the catalytic triad Cys145–His41–Asp187 of SARS-CoV-2 Mpro plays important role in the activation of PF-07321332 covalent inhibitor, which renders the deprotonation of Cys145 and, thus, facilitates further reaction. Our results are definitely beneficial for better understanding on the inhibition mechanism and designing new effective inhibitors for SARS-CoV-2 Mpro.

scholarly journals In Silico Investigation on the Binding of Organoselenium Compounds with Target Proteins of SARS-CoV-2 Infection Cycle

2020 ◽  
Author(s):  
Beena Gobind Singh ◽  
Amit Kunwar
Keyword(s):  
Host Protein ◽  
Infection Cycle ◽  
Autodock Vina ◽  
Organoselenium Compounds ◽  
Target Proteins ◽  
Main Protease ◽  
Docking Approach ◽  
Docking Calculations ◽  
Aromatic Amide ◽  
Candidate Molecule

<p>Since the outbreak of coronavirus disease 2019 (COVID-19), researchers have been investigating the potential of several low molecular weight compounds from both natural and synthetic origins to design anti-viral drugs against SARS-CoV-2. On similar lines, the present study is aimed to evaluate different organoselenium compounds and their sulfur analogues by using a molecular docking approach to inhibit viral proteins like spike (S) glycoprotein (PDB code: 6VXX) and main protease (M<sup>pro</sup>) (PDB code: 6LU7) and a host protein, Furin (PDB code: 5MIM), all of which are known to play significant role in SARS-CoV-2 infection cycle. The organoselenium compounds used in the study are mostly <i>in-house</i> synthesized including simple selenium containing amino acids and their derivatives and selenopyridines and their derivatives. The docking calculations were performed using AutoDock Vina. In brief, organoselenium compounds showed stronger binding with the target proteins as compared to their sulfur analogue, except oxidized glutathione. Notably, the most potent docked ligands shared a common structural feature of aromatic amide moieties connected by diselenide bridge. Further, the compounds ebselen diselenide (EbSeSeEb) and nicotinamide diselenide (NictSeSeNict) exhibited the highest binding affinity (in range of ~10<sup>5 </sup>µM<sup>-1</sup>) to all the above three proteins. Thus, the present investigation highlights the influence of structure and substitution of organoselenium compound on their binding with the SARS-CoV-2 proteins and proposes NictSeSeNict as a candidate molecule for evaluating anti-viral activity against SARS-CoV-2 using preclinical biological models.</p>

scholarly journals In Silico Investigation on the Binding of Organoselenium Compounds with Target Proteins of SARS-CoV-2 Infection Cycle

2020 ◽  
Author(s):  
Beena Gobind Singh ◽  
Amit Kunwar
Keyword(s):  
Host Protein ◽  
Infection Cycle ◽  
Autodock Vina ◽  
Organoselenium Compounds ◽  
Target Proteins ◽  
Main Protease ◽  
Docking Approach ◽  
Docking Calculations ◽  
Aromatic Amide ◽  
Candidate Molecule

<p>Since the outbreak of coronavirus disease 2019 (COVID-19), researchers have been investigating the potential of several low molecular weight compounds from both natural and synthetic origins to design anti-viral drugs against SARS-CoV-2. On similar lines, the present study is aimed to evaluate different organoselenium compounds and their sulfur analogues by using a molecular docking approach to inhibit viral proteins like spike (S) glycoprotein (PDB code: 6VXX) and main protease (M<sup>pro</sup>) (PDB code: 6LU7) and a host protein, Furin (PDB code: 5MIM), all of which are known to play significant role in SARS-CoV-2 infection cycle. The organoselenium compounds used in the study are mostly <i>in-house</i> synthesized including simple selenium containing amino acids and their derivatives and selenopyridines and their derivatives. The docking calculations were performed using AutoDock Vina. In brief, organoselenium compounds showed stronger binding with the target proteins as compared to their sulfur analogue, except oxidized glutathione. Notably, the most potent docked ligands shared a common structural feature of aromatic amide moieties connected by diselenide bridge. Further, the compounds ebselen diselenide (EbSeSeEb) and nicotinamide diselenide (NictSeSeNict) exhibited the highest binding affinity (in range of ~10<sup>5 </sup>µM<sup>-1</sup>) to all the above three proteins. Thus, the present investigation highlights the influence of structure and substitution of organoselenium compound on their binding with the SARS-CoV-2 proteins and proposes NictSeSeNict as a candidate molecule for evaluating anti-viral activity against SARS-CoV-2 using preclinical biological models.</p>

Regioselective C–H selenylation of heteroarenes under metal-free conditions

2021 ◽  
Vol 25 ◽  
Author(s):  
Ricardo F. Schumacher ◽  
Roberta Cargnelutti ◽  
Adriane Sperança ◽  
Jean C. Kazmierczak ◽  
Thiago Anjos ◽  
...  
Keyword(s):  
Supramolecular Chemistry ◽  
Organic Synthesis ◽  
Medicinal Chemistry ◽  
Optoelectronic Devices ◽  
Literature Survey ◽  
Organoselenium Compounds ◽  
Metal Free ◽  
The Past ◽  
Target Molecules ◽  
Safe Access

Selenium-containing heteroarenes consist of a synthetically valuable family of compounds that found applications in many different areas, such as organic synthesis, medicinal chemistry, supramolecular chemistry, and optoelectronic devices construction. Over the past decade, many advances have been achieved to the synthesis of these substances, and this review aims to cover a literature survey of the direct selenylation of heteroarenes under metal-free conditions, which represents one of the most powerful synthetic strategies for the preparation of those target molecules. The construction of new C-Se bonds through selective C-H functionalization reactions has become useful and atom-economical. The widespread adoption of metal-free approaches has emerged as versatile, sustainable, and safe access to these organoselenium compounds. Among the features of these new protocols are the use of mild oxidants and halogen-based catalysts, inorganic bases, as well as photo-induced reactions, and electrosynthesis.

Analyzing the Potential Benefit of Microcomputer Use for Teaching Figurative Language

1992 ◽  
Vol 1 (2) ◽  
pp. 36-43 ◽  
Author(s):  
Marilyn A. Nippold ◽  
Ilsa E. Schwarz ◽  
Molly Lewis
Keyword(s):  
Language Learning ◽  
Children And Adolescents ◽  
Standardized Tests ◽  
Figurative Language ◽  
Language Intervention ◽  
School Age Children ◽  
Educational Materials ◽  
Language Learning Disabilities ◽  
Promising Application ◽  
Experience Difficulty

Microcomputers offer the potential for increasing the effectiveness of language intervention for school-age children and adolescents who have language-learning disabilities. One promising application is in the treatment of students who experience difficulty comprehending figurative expressions, an aspect of language that occurs frequently in both spoken and written contexts. Although software is available to teach figurative language to children and adolescents, it is our feeling that improvements are needed in the existing programs. Software should be reviewed carefully before it is used with students, just as standardized tests and other clinical and educational materials are routinely scrutinized before use. In this article, four microcomputer programs are described and evaluated. Suggestions are then offered for the development of new types of software to teach figurative language.

Sign in / Sign up

Export Citation Format

Share Document