Molecular docking and dynamic simulation of approved drugs targeting against spike protein (6VXX) of 2019-nCoV (novel coronavirus)

The 2019-nCoV has triggered a global public health emergency due to its rapid spread, resulting in a pandemic situation. Because of its ability to bind with the host cell receptor ACE-2, the spike protein of the 2019-nCoV is a critical factor in viral infection. The current study aims to investigate the molecular-docking of the spike protein (6VXX) using PyRx for FDA-approved drugs available for the treatment of SARS-1 and MERS, with the hypothesis that these drugs could be suggested for the treatment of 2019-nCoV or not. A phylogenetic analysis of 2019-nCoV in relation to SARS-1 and MERS confirmed the validation. The positive result urged the Multiple Sequence Alignment analysis of the top five affected countries, with China serving as a control, using WHO available reference data to determine the rate of mutant variation. The docking results revealed that the top ten drugs with the highest binding affinity rate are also used for Hepatitis-C virus treatment, and the Molecular Dynamic Simulation was carried out for the drug Paritaprevir, which had the highest binding affinity rate, using Gromacs. The results indicated that the drug Paritaprevir could be used as a potential target against the 2019-nCoV Spike protein.     

Insights into the inhibitory potential of selective phytochemicals against Mpro of 2019-nCoV: a computer-aided study

Structural Chemistry - At the end of December 2019, a novel strain of coronavirus, given the name of 2019-nCoV, emerged for exhibiting symptoms of severe acute respiratory syndrome. The virus is...     

Resilient and agile engineering solutions to address societal challenges such as coronavirus pandemic

The world is witnessing tumultuous times as major economic powers including the US, UK, Russia, India, and most of Europe continue to be in a state of lockdown. The worst-hit sectors due to this lockdown are sales, production (manufacturing), transport (aerospace and automotive) and tourism. Lockdowns became necessary as a preventive measure to avoid the spread of the contagious and infectious “Coronavirus Disease 2019” (COVID-19). This newly identified disease is caused by a new strain of the virus being referred to as Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS CoV-2; formerly called 2019-nCoV). We review the current medical and manufacturing response to COVID-19, including advances in instrumentation, sensing, use of lasers, fumigation chambers and development of novel tools such as lab-on-the-chip using combinatorial additive and subtractive manufacturing techniques and use of molecular modelling and molecular docking in drug and vaccine discovery. We also offer perspectives on future considerations on climate change, outsourced versus indigenous manufacturing, automation, and antimicrobial resistance. Overall, this paper attempts to identify key areas where manufacturing can be employed to address societal challenges such as COVID-19.     

双子表面活性剂及其抗菌性能

Gemini surfactants contain two hydrophilic and two hydrophobic groups connected by a linkage close to the hydrophilic groups. Gemini surfactants have lower critical micelle concentration, higher surface activity, greater efficiency in decreasing the surface tension of water and the interfacial tension between water and oil, and better water solubility than conventional surfactants. Gemini surfactants are widely used as sterilizing, bacteriostatic, anti-foaming, and drug release agents in various enterprises including food production and industrial cleaning. They, therefore, play a very important social, economic, and industrial role. This paper briefly summarizes gemini surfactant development, structure, self-assembly, activity, classification, and characteristics, as well as focuses on the antibacterial mechanisms of these compounds. It is expected that the antibacterial properties of gemini surfactants may help slow the spread of the novel coronavirus (2019-nCoV).     

Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (K_D, μM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 μM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.     

The role of biosensors in coronavirus disease-2019 outbreak

Herein, we have summarized and argued about biomarkers and indicators used for the detection of severe acute respiratory syndrome coronavirus 2. Antibody detection methods are not considered suitable to screen individuals at early stages and asymptomatic cases. The diagnosis of coronavirus disease 2019 using biomarkers and indicators at point-of-care level is much crucial. Therefore, it is urgently needed to develop rapid and sensitive detection methods which can target antigens. We have critically elaborated key role of biosensors to cope the outbreak situation. In this review, the importance of biosensors including electrochemical, surface enhanced Raman scattering, field-effect transistor, and surface plasmon resonance biosensors in the detection of severe acute respiratory syndrome coronavirus 2 has been underscored. Finally, we have outlined pros and cons of diagnostic approaches and future directions.     

Innate immune sensing of coronavirus and viral evasion strategies

The innate immune system is the first line of the host defense program against pathogens and harmful substances. Antiviral innate immune responses can be triggered by multiple cellular receptors sensing viral components. The activated innate immune system produces interferons (IFNs) and cytokines that perform antiviral functions to eliminate invading viruses. Coronaviruses are single-stranded, positive-sense RNA viruses that have a broad range of animal hosts. Coronaviruses have evolved multiple means to evade host antiviral immune responses. Successful immune evasion by coronaviruses may enable the viruses to adapt to multiple species of host organisms. Coronavirus transmission from zoonotic hosts to humans has caused serious illnesses, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease-2019 (COVID-19), resulting in global health and economic crises. In this review, we summarize the current knowledge of the mechanisms underlying host sensing of and innate immune responses against coronavirus invasion, as well as host immune evasion strategies of coronaviruses.Subject terms: Infection, Pattern recognition receptors, Immune evasion     

基于成簇的规则间隔短回文重复序列的严重急性呼吸综合征冠状病毒2检测的最新进展北大核心CSCD

严重急性呼吸综合征冠状病毒2(SARS-CoV-2)导致的新冠肺炎(COVID-19)迅速蔓延全球,给全球公共卫生系统带来了挑战。由于逆转录-定量聚合酶链反应(RT-qPCR)和抗原测试的普遍适用性和灵敏度较差,并且具有不同突变的SARS-CoV-2变体持续的出现,给疫情防控带来了更大的挑战,因此,高灵敏度、无需设备并且能够区分SARS-CoV-2变体的诊断方法亟须发展。基于成簇的规则间隔短回文重复序列(CRISPR)的诊断对设备要求低,具有可编程性、灵敏性和易用性,已经发展出多种核酸检测工具用于传染病的诊断,其在临床上具有巨大的应用潜力。文章聚焦于近期发表的基于CRISPR实现SARS-CoV-2检测和变体区分的最新技术,总结其特点并对其发展进行了展望。     

A computational analysis of molecular evolution for virulence genes of zoonotic novel coronavirus (COVID-19)

Zoonotic Novel coronavirus disease 2019 (COVID-19) is highly pathogenic and transmissible considered as emerging pandemic disease. The virus belongs from a large virus Coronaviridae family affect respiratory tract of animal and human likely originated from bat and homology to SARA-CoV and MERS-CoV. The virus consists of single-stranded positive genomic RNA coated by nucleocapsid protein. The rate of mutation in any virulence gene may influence the phenomenon of host radiation. We have studied the molecular evolution of selected virulence genes (HA, N, RdRP and S) of novel COVID-19. We used a site-specific comparison of synonymous (silent) and non-synonymous (amino acid altering) nucleotide substitutions. Maximum Likelihood genealogies based on differential gamma distribution rates were used for the analysis of null and alternate hypothesis. The null hypothesis was found more suitable for the analysis using Likelihood Ratio Test (LRT) method, confirming higher rate of substitution. The analysis revealed that RdRP gene had the fastest rate evolution followed by HA gene. We have also reported the new motifs for different virulence genes, which are further useful to design new detection and diagnosis kit for COVID -19.     

分离技术在新型冠状病毒研究和防疫检测中的应用

新型冠状病毒肺炎(COVID-19)疫情的爆发给世界公共卫生安全带来前所未有的挑战.随着新型冠状病毒(SARS-CoV-2)相关研究的不断深入,众多分析检测技术相继被应用,推动了病毒检测、疫苗和创新疗法的研发,从而使疫情早日得到控制.分离技术作为生命科学、医学、药学领域的关键技术,操作简单,分离效率高,选择性强,在新型...     

Exogenous pulmonary surfactant: A review focused on adjunctive therapy for severe acute respiratory syndrome coronavirus 2 including SP-A and SP-D as added clinical marker

Type I and type II pneumocytes are two forms of epithelial cells found lining the alveoli in the lungs. Type II pneumocytes exclusively secrete ‘pulmonary surfactants,’ a lipoprotein complex made up of 90% lipids (mainly phospholipids) and 10% surfactant proteins (SP-A, SP-B, SP-C, and SP-D). Respiratory diseases such as influenza, severe acute respiratory syndrome coronavirus infection, and severe acute respiratory syndrome coronavirus 2 infection are reported to preferentially attack type II pneumocytes of the lungs. After viral invasion, consequent viral propagation and destruction of type II pneumocytes causes altered surfactant production, resulting in dyspnea and acute respiratory distress syndrome in patients with coronavirus disease 2019. Exogenous animal-derived or synthetic pulmonary surfactant therapy has already shown immense success in the treatment of neonatal respiratory distress syndrome and has the potential to contribute efficiently toward repair of damaged alveoli and preventing severe acute respiratory syndrome coronavirus 2–associated respiratory failure. Furthermore, early detection of surfactant collectins (SP-A and SP-D) in the circulatory system can be a significant clinical marker for disease prognosis in the near future.     

Kinetics of lipid layer formation at interfaces

A formal kinetic model of lipid layer formation at an interface in contact with a liposomal suspension is developed and investigated. Neglecting diffusion (for sufficiently high bulk concentrations) the kinetic scheme consists of two consecutive processes: (I) irreversible transformation of ‘soluble’ intact vesicles from the ‘subsurface’ layer into ‘adsorbed’ ones (‘defected’ or ‘ruptured’ liposomes, ‘mesophases’); and (II) irreversible transformation of the ‘adsorbed’ vesicles into a lipid monolayer. The resulting set of two differential equations is analyzed making use of the ‘steady-state concentration’ approach (with ‘adsorbed’ vesicles as intermediate compound). Numerical results illustrate the predicted kinetic behavior which depends on the relative magnitude of the rates of the two consecutive processes. Approximate analytical solutions in the case of a much slower process I are obtained in some limiting cases. The model is used to estimate rate constants from previously established experimental kinetic data at the air/water interface.     

Combinatorial enumeration of ethane derivatives as three-dimensional chemical structures,not as graphs. A systematic approach for enumerating and characterizing stereoisomers of tartaric acids and related compounds

Fujita’s proligand method is applied to the enumeration of ethane derivatives, where the counting of stereoisomers of tartaric acids is examined in detail as a probe for testing the versatility of the method. The cycle index with chirality fittingness (CI-CF) for enumerating ethane derivatives is obtained by Fujita’s proligand method and compared with the CI-CF derived alternatively by the direct calculation of permutations of substitution positions. The two CI-CFs are identical with each other so that the methodology underlying in Fujita’s method is demonstrated in a concrete fashion. The enumeration results are compared with those derived by Pólya’s corona. Fujita’s proligand method is shown to be capable of enumerating stereoisomers, whereas Pólya’s corona is concluded to enumerate graphs, but not stereoisomers. The conceptually change from graphs to three-dimensional (3D) chemical structures is discussed, where the superiority of Fujita’s proligand method is demonstrated.     

Role of the Residue Q1919 in Increasing Kinase Activity of G2019S LRRK2 Kinase: A Computational Study

Mutations in multi-domain leucine-rich repeat kinase 2 (LRRK2) have been an interest to researchers as these mutations are associated with Parkinson's disease. G2019S mutation in LRRK2 kinase domain leads to the formation of additional hydrogen bonds by S2019 which results in stabilization of the active state of the kinase, thereby increasing kinase activity. Two additional hydrogen bonds of S2019 are reported separately. Here, a mechanistic picture of the formation of additional hydrogen bonds of S2019 with Q1919 (also with E1920) is presented using ‘active’ Roco4 kinase as a homology model and its relationship with the stabilization of the ‘active’ G2019S LRRK2 kinase. A conformational flipping of residue Q1919 was found which helped to form stable hydrogen bond with S2019 and made ‘active’ state more stable in G2019S LRRK2. Two different states were found within the ‘active’ kinase with respect to the conformational change (flipping) in Q1919. Two doubly-mutated systems, G2019S/Q1919A and G2019S/E1920 K, were studied separately to check the effect of Q1919 and E1920. For both cases, the stable S2 state was not formed, leading to a decrease in kinase activity. These results indicate that both the additional hydrogen bonds of S2019 (with Q1919 and E1920) are necessary to stabilize the active G2019S LRRK2.     

L’importance des phénomènes d’oxydo-réduction dans le verreImportance of oxidoreduction phenomena in glass.

Oxydo-reduction phenomenon concerns glass manufacturing as well as its properties. Various oxidation scales have been used by glassmakers, the most widely used being the ratio between Fe²⁺ and the total iron content. Comparisons are made with others, such as the partial pressure of oxygen or the redox potential. The influence of the chemical composition of the glass is also studied as well as that of the temperature, through the results obtained in Saint-Gobain Recherche and in other laboratories. In industrial glass manufacturing, the oxidation equilibrium is usually achieved during the fining process, an intense ‘bubbling’ being necessary to obtain a homogeneous glass. Thus, the oxidoreduction state of the glass does not depend on the atmosphere under which it was made, but depends on the mixture of gases generated during the fining process, which is described through the reactions generated by the two main fining systems, arsenic oxide or antimony oxide + sodium nitrate and sodium sulphate + a reducing agent. The former provides oxygen and the latter, a mixture of oxygen and sulphur dioxide. Consequently, a glass melted with arsenic oxide is more oxidised than a glass melted with sodium sulphate. The equilibrium constant used to interpret the latter system, mostly used for soda lime silica glasses fining, is given as a function of the temperature and some of the consequences are examined. Obviously, the coloration by iron oxide impurities is influenced by the manufacturing process. Some other colouring oxides are submitted to a change of oxidation state and thus to a modification of their colouring action. A quick review is done of the transition metal coloration, of the electron-charge-transfer absorption due to sulphides or selenides, and of aggregate formation inducing the well-known red ruby glass, for instance.

Résumé

Les phénomènes d’oxydo-réduction concernent aussi bien l’élaboration du verre que ses propriétés. Plusieurs échelles d’oxydo-réduction ont été utilisées par les verriers, la plus courante étant le rapport entre Fe²⁺ et la teneur totale en fer. Nous faisons la comparaison entre les différents systèmes, comme la pression partielle d’oxygène. Dans l’élaboration des verres industriels, l’équilibre redox est réalisé habituellement pendant le processus d’affinage, un « bullage » intense étant indispensable à l’obtention d’un verre homogène. L’état redox du verre ne dépend pas de l’atmosphère sous laquelle il a été élaboré, mais du mélange de gaz généré durant le processus d’affinage. Les deux systèmes affinants principaux sont l’oxyde d’arsenic ou d’antimoine couplé au nitrate de sodium ou bien le sulfate de sodium couplé à un agent réducteur. Le premier génère de l’oxygène et le second un mélange d’oxygène et de dioxyde de soufre. En conséquence, un verre élaboré avec de l’oxyde d’arsenic est plus oxydé qu’un verre élaboré avec du sulfate de sodium. La coloration par l’impureté oxyde de fer est évidemment fortement influencée par le procédé. D’autres oxydes colorants subissent aussi des changements d’état d’oxydo-réduction et voient leur action colorante modifiée en fonction des conditions d’élaboration.     

Facile route to synthesis of functionalised poly(methylalkoxy)siloxane under mild and aerobic conditions in the presence of platinum catalysts

A facile and high yield method of synthesis of novel and functional poly(methylalkoxy) siloxanes is reported. The Si–H groups of poly(methylhydrogen) siloxanes (PMHS) were treated with various simple (primary, secondary, tertiary) alcohols (1a–10a) in the presence of platinum based catalysts (Speier’s and Karstedt’s catalysts). Also oxyethylene, aldehyde, epoxide, halogen and allyl grafted polysiloxane were smoothly and quantitatively prepared by the alcoholysis between linear siloxanes polymer and functional alcohols (11a–20a) with use of Karstedt’s catalysts. It is found that alcoholysis reaction in the presence of the Karstedt’s catalyst proceed faster than Speier’s catalyst .In addition, the rate of alcoholysis reaction is dependent on amount of the catalyst and reaction temperature. The polymers prepared were characterized by IR, NMR spectroscopy and GPC analysis.     

Correlations between electrochemical and spectral properties of alkyl-substituted diphthalocyanine lanthanide complexes

The electrochemical behavior and spectral properties of a series of symmetrical 2,3,9,10,16,17,23,24,2’,3’,9’, 10’,16’,17’,23’,24’-hexadecaalkyl-substituted lanthanide complexes (R₈Pc)₂Ln (R = H, Me, Et, Buⁿ; Ln = Eu, Dy, Lu) were studied. Regularities of changing the parameters under study were established, depending on the nature of lanthanide and substituents in the phthalocyanine macroligands. The position of the intervalence band of the complexes in the near-IR region depends on the effective distance between the macroligands and also on the electronic effect of the substituents. Correlations between the electrochemical and spectral properties of the complexes were found.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 184–189, January, 2005.     

Inhibition of SARS coronavirus helicase by bismuth complexes

A series of bismuth complexes were synthesized and characterized, and most of them exhibited inhibition against the SARS coronavirus helicase ATPase and duplex-unwinding activities at micromolar concentrations.     

The synergistic effect of cobalt-dicarbollide anions on the extraction of M lanthanide cations by Calix[4]arenes: a molecular dynamics study at the water–‘oil’ interface

We report molecular dynamics studies on the effect of CCD^– (chlorinated cobalt-dicarbollide) anions on the Eu³⁺ lanthanide cation extraction by a calix[4]arene-CMPO ligand L, focusing on the water–‘oil’ interface, where ‘oil’ is modelled by chloroform. The free L ligand and its EuL³⁺ complex are found to adsorb and to concentrate at the interface, but are too hydrophilic to be extracted. Addition of CCD^– anions in diluted conditions (either covalent linked to L or as separated CCD^– H₃O⁺ ions) also leads to adsorption of these species at the interface. However, at high concentrations, CCD^– anions saturate the interface and promote the extraction of EuL³⁺ to the oil phase. Another important feature concerns the uncomplexed Eu(CCD)₃ salt: accumulation of CCD^– anions at the interface creates a negative potential which attracts the hydrated Eu³⁺ ions, therefore facilitating their complexation by interfacial ligands. These features allow us to better understand the synergistic effect of lipophilic anions in the assisted liquid-liquid extraction of trivalent M³⁺ lanthanide or actinide cations. To cite this article: B. Coupez, G. Wipf, C. R. Chimie 7 (2004).

Résumé

Synergie due aux anions dicarbollides lors de l’extraction d’ions lanthanides M³⁺ par des calix[4]arènes : simulations de dynamique moléculaire à l’interface eau–« huile ». Nous étudions par simulations de dynamique moléculaire l’effet de synergie dû aux anions CCD^– (cobalt-dicarbollides) lors de l’extraction de Eu³⁺ par un calix [4]arène L, en se focalisant sur l’interface eau–« huile », l’huile étant modélisée par du chloroforme. On montre que le ligand L et son complexe EuL³⁺ s’adsorbent à l’interface, mais sont trop hydrophiles pour être extraits. L’addition d’anions CCD^– (qu’ils soient sous la forme d’ions CCD^– H₃O⁺ séparés ou greffés de façon covalente au calixarène) conduit aussi à l’adsorption de ces espèces à l’interface. Cependant, aux plus fortes concentrations, les anions CCD^– saturent l’interface et induisent l’extraction du complexe EuL³⁺ vers l’huile. Un autre résultat remarquable concerne les sels Eu(CCD)₃ : l’accumulation des anions CCD^– à l’interface y crée un potentiel négatif, ce qui attire les cations Eu³⁺ et facilite ainsi leur complexation par des ligands à l’interface. Ces résultats permettent de mieux comprendre l’effet de synergie dû aux anions CCD^– lors de l’extraction d’ions lanthanides ou actinides M³⁺ et, d’une manière générale, ce qui se passe à l’interface entre l’eau et des liquides non miscibles. Pour citer cet article : B. Coupez, G. Wipf, C. R. Chimie 7 (2004).