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1.
Journal of Chemical Education ; 99(9):3211-3217, 2022.
Article in English | Web of Science | ID: covidwho-2016518

ABSTRACT

We describe a remote pedagogical approach based on chemical thinking to study metal-carbonyl complexes by analyzing simulated IR spectra. The proposed approach, implemented due to the COVID-19 pandemic, can be employed in classrooms that have very limited laboratory equipment for evaluating toxic metal-carbonyl compounds, as well as for synthesizing compounds that have not been reported . The method, consisting of a class lecture accompanied by a remote computational activity , aims to provide students with the ability to assemble concepts from different fields, such as organometallic chemistry and analytical chemistry, while taking advantage of computational methods to answer higher level questions. We evaluated whether analyzing the nature of M-CO bonding was appropriate for achieving these educational goals. Octahedral compounds of the M(CO)(6) and M(CO)(4)L-2 type, bearing a variety of metal centers (M = Cr, Mo, W, V, Mn and Fe) and ligands (L = phosphines and phosphites), as well as bimetallic Fe-2(CO)(9), were compared, showing how these modifications affect M-CO bonding. After the didactic session, attended by second-year and upper-division students of Facultad de Quimica at UNAM, an evaluation and survey showed that students improved their understanding of the subject when they obtained and visualized IR spectra, also exhibiting greater confidence and enthusiasm for addressing challenging topics. The combination of computational results, spectroscopic analysis, and organometallic theory represents an efficient and clear procedure for implementing chemical thinking, regardless of the difficulties posed by the COVID-19 pandemic.

2.
22nd International Conference on Computational Science and Its Applications , ICCSA 2022 ; 13382 LNCS:264-274, 2022.
Article in English | Scopus | ID: covidwho-2013919

ABSTRACT

A new highly efficient GPU-equipped computing platform for studying the molecular inhibition mechanisms of the Sars-Cov-2 virus by natural compounds and aptamers has been installed and configured. Studies will be carried out by means of molecular dynamics methods and programs. For this reason, we have assembled specific hardware components into a 4U rack, together with a NVIDIA RTX 3060 GPU for speeding up molecular dynamics calculations and visualizing their outcomes. In fact, not only computational resources, in terms of computing power and execution times, are needed by molecular dynamics programs adopted by us, but also a system allowing the rendering and visualization of large biomolecules and their trajectories, such as viruses and proteins, represents a key factor for our work. Details about platform implementation and preliminary tests carried out are discussed. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

3.
Computers, Materials, & Continua ; 73(3):5717-5734, 2022.
Article in English | ProQuest Central | ID: covidwho-1975811

ABSTRACT

In 2020, the reported cases were 0.12 million in the six regions to the official report of the World Health Organization (WHO). For most children infected with leprosy, 0.008629 million cases were detected under fifteen. The total infected ratio of the children population is approximately 4.4 million. Due to the COVID-19 pandemic, the awareness programs implementation has been disturbed. Leprosy disease still has a threat and puts people in danger. Nonlinear delayed modeling is critical in various allied sciences, including computational biology, computational chemistry, computational physics, and computational economics, to name a few. The time delay effect in treating leprosy delayed epidemic model is investigated. The whole population is divided into four groups: those who are susceptible, those who have been exposed, those who have been infected, and those who have been vaccinated. The local and global stability of well-known conclusions like the Routh Hurwitz criterion and the Lyapunov function has been proven. The parameters’ sensitivity is also examined. The analytical analysis is supported by computer results that are presented in a variety of ways. The proposed approach in this paper preserves equilibrium points and their stabilities, the existence and uniqueness of solutions, and the computational ease of implementation.

4.
Molecules ; 27(13)2022 Jun 24.
Article in English | MEDLINE | ID: covidwho-1911487

ABSTRACT

Ethnopharmacology, through the description of the beneficial effects of plants, has provided an early framework for the therapeutic use of natural compounds. Natural products, either in their native form or after crude extraction of their active ingredients, have long been used by different populations and explored as invaluable sources for drug design. The transition from traditional ethnopharmacology to drug discovery has followed a straightforward path, assisted by the evolution of isolation and characterization methods, the increase in computational power, and the development of specific chemoinformatic methods. The deriving extensive exploitation of the natural product chemical space has led to the discovery of novel compounds with pharmaceutical properties, although this was not followed by an analogous increase in novel drugs. In this work, we discuss the evolution of ideas and methods, from traditional ethnopharmacology to in silico drug discovery, applied to natural products. We point out that, in the past, the starting point was the plant itself, identified by sustained ethnopharmacological research, with the active compound deriving after extensive analysis and testing. In contrast, in recent years, the active substance has been pinpointed by computational methods (in silico docking and molecular dynamics, network pharmacology), followed by the identification of the plant(s) containing the active ingredient, identified by existing or putative ethnopharmacological information. We further stress the potential pitfalls of recent in silico methods and discuss the absolute need for in vitro and in vivo validation as an absolute requirement. Finally, we present our contribution to natural products' drug discovery by discussing specific examples, applying the whole continuum of this rapidly evolving field. In detail, we report the isolation of novel antiviral compounds, based on natural products active against influenza and SARS-CoV-2 and novel substances active on a specific GPCR, OXER1.


Subject(s)
Biological Products , COVID-19 , Biological Products/chemistry , COVID-19/drug therapy , Drug Discovery/methods , Ethnopharmacology/methods , Plants/chemistry , SARS-CoV-2
5.
Moroccan Journal of Chemistry ; 10(1):037-049, 2022.
Article in English | Scopus | ID: covidwho-1893748

ABSTRACT

Computational Chemistry is a branch of chemistry that employs computer simulations to assist in resolving problems regarding chemistry. The goal of this research is to combine mapping analysis from VOSviewer software to analyze bibliometrics in Computational Chemistry field. The data were obtained through the use of a reference manager application with "Computational Chemistry" as the keyword. We collected 1000 articles published between 2017 - 2021 in the search results. According to the findings, research in the field of Computational Chemistry decreased from 2018 to 2020, but increased since 2021. The primary reason for this is that the pandemic has had a significant impact on Computational Chemistry, which is related to laboratory engineering and molecular modeling. This study demonstrates the value of bibliometric analysis in providing analytical data about a phenomenon. The findings of this study are beneficial for future research to find potential areas of Computational Chemistry that can be studied further, due to the discovery of less-researched areas. © 2022. All Rights Reserved.

6.
Natural Product Communications ; 17(4), 2022.
Article in English | Scopus | ID: covidwho-1846642

ABSTRACT

Jiedu Huoxue Decoction (JHD), a recommended traditional prescription for patients with severe COVID-19, has appeared in the treatment protocols in China. Based on bioinformatics and computational chemistry methods, including molecular docking, molecular dynamics (MD) simulation, and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) calculation, we aimed to reveal the mechanism of JHD in treating severe COVID-19. The compounds in JHD were obtained and screened on TCMSP, SwissADME, and ADMETLab platforms. The compound targets were obtained from TCMSP and STITCH, while COVID-19 targets were obtained from Genecards and NCBI. The protein-protein interaction network was constructed by using STRING. Gene Ontology (GO) and KEGG enrichment were performed with ClueGO and R language. AutoDock vina was employed for molecular docking. 100 ns MD simulation of the optimal docking complex was carried out with AmberTools 20. A total of 84 compounds and 29 potential targets of JHD for COVID-19 were collected. The key phytochemicals included quercetin, luteolin, β-sitosterol, puerarin, stigmasterol, kaempferol, and wogonin, which could regulate the immune system. The hub genes included IL6, IL10, VEGFA, IL1B, CCL2, HMOX1, DPP4, and ACE2. ACE2 and DPP4 were related to SARS-CoV-2 entering cells. GO and KEGG analysis showed that JHD could intervene in cytokine storm and endothelial proliferation and migration related to thrombosis. The molecular docking, 100 ns MD simulation, and MM/GBSA calculation confirmed that targets enriched in the COVID-19 pathway had high affinities with related compounds, and the conformations of the puerarin-ACE2, quercetin-EGFR, luteolin-EGFR, and quercetin-IL1B complexes were stable. In a word, JHD could treat COVID-19 by intervening in cytokine storm, thrombosis, and the entry of SARS-CoV-2, while regulating the immune system. These mechanisms were consistent with JHD's therapeutic concept of “detoxification” and “promoting blood circulation and removing blood stasis” in treating COVID-19. The research provides a theoretical basis for the development and application of JHD. © The Author(s) 2022.

7.
Education Sciences ; 12(4):252, 2022.
Article in English | ProQuest Central | ID: covidwho-1809780

ABSTRACT

Computational and atmospheric chemistry are two important branches of contemporary chemistry. With the present topical nature of climate change and global warming, it is more crucial than ever that students are aware of and exposed to atmospheric chemistry, with an emphasis on how modeling may aid in understanding how atmospherically relevant chemical compounds interact with incoming solar radiation. Nonetheless, computational and atmospheric chemistry are under-represented in most undergraduate chemistry curricula. In this manuscript, we describe a simple and efficient method for simulating the electronic absorption spectral profiles of atmospherically relevant molecules that may be utilized in an undergraduate computer laboratory. The laboratory results give students hands-on experience in computational and atmospheric chemistry, as well as electronic absorption spectroscopy.

8.
J Cheminform ; 14(1): 22, 2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1785168

ABSTRACT

We present several workflows for protein-ligand docking and free energy calculation for use in the workflow management system Galaxy. The workflows are composed of several widely used open-source tools, including rDock and GROMACS, and can be executed on public infrastructure using either Galaxy's graphical interface or the command line. We demonstrate the utility of the workflows by running a high-throughput virtual screening of around 50000 compounds against the SARS-CoV-2 main protease, a system which has been the subject of intense study in the last year.

9.
Front Mol Biosci ; 9: 781039, 2022.
Article in English | MEDLINE | ID: covidwho-1775718

ABSTRACT

We urgently need to identify drugs to treat patients suffering from COVID-19 infection. Drugs rarely act at single molecular targets. Off-target effects are responsible for undesirable side effects and beneficial synergy between targets for specific illnesses. They have provided blockbuster drugs, e.g., Viagra for erectile dysfunction and Minoxidil for male pattern baldness. Existing drugs, those in clinical trials, and approved natural products constitute a rich resource of therapeutic agents that can be quickly repurposed, as they have already been assessed for safety in man. A key question is how to screen such compounds rapidly and efficiently for activity against new pandemic pathogens such as SARS-CoV-2. Here, we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-CoV-2. We show that the shortlist of 84 candidates with the strongest predicted binding affinities is highly enriched (≥25%) in compounds experimentally validated in vivo or in vitro to have activity in SARS-CoV-2. The top candidates also include drugs and natural products not previously identified as having COVID-19 activity, thereby providing leads for experimental validation. This predictive in silico screening pipeline will be valuable for repurposing existing drugs and discovering new drug candidates against other medically important pathogens relevant to future pandemics.

10.
chemRxiv; 2022.
Preprint in English | ChemRxiv | ID: ppcovidwho-329457

ABSTRACT

Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604, the NK1 antagonist, aprepitant, the trypanocidal drug, aminoquinuride, the analgesic antrafenine, the anticancer intercalator, epirubicin, the antihistamine, fexofenadine, and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments

11.
Int J Mol Sci ; 23(1)2021 Dec 27.
Article in English | MEDLINE | ID: covidwho-1580698

ABSTRACT

In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly expressed as the half-maximal inhibitory concentration (IC50) value, against M-pro from SARS-CoV-2 has been determined. Several covalent warheads are used to treat covalent and non-covalent inhibitors separately. Chemical space, the variation of the IC50 inhibitory activity when measured by different methods or laboratories, and the influence of 1,4-dithiothreitol (DTT) are discussed. When available, we have collected the values of inhibition of viral replication measured with a cellular antiviral assay and expressed as half maximal effective concentration (EC50) values, and their possible relationship to inhibitory potency against M-pro is analyzed. Finally, the most potent covalent and non-covalent inhibitors that simultaneously inhibit the SARS-CoV-2 M-pro and the virus replication in vitro are discussed.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/chemistry , Databases, Pharmaceutical , Enzyme Assays/methods , Inhibitory Concentration 50 , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Virus Replication/drug effects
12.
ChemistrySelect ; 6(46):13363-13381, 2021.
Article in English | Wiley | ID: covidwho-1557791

ABSTRACT

Drug development is a tedious, expensive and time consuming process that is accompanied with huge amount of uncertainty due to very low success rate using conventional methods. However, in-silico techniques have helped society in drug designing and repurposing at minimal cost by shortlisting potentially hit compounds from huge libraries in a short span of time. This computational methodology has made a prominent contribution in the virtual screening of therapeutically relevant drugs for various viral diseases. It has helped in providing relevant information regarding drug-target interaction and mechanism through which we can modify our drug compound for better efficiency. In-silico tools additionally helps in predicting toxicity and pharmacokinetics, which can further help in clearing trials and approval. The recent outbreak of novel coronavirus (COVID-19) has resulted in a huge number of deaths and affected the economy of the world adversely. Computational methods have played a major role in shortlisting compounds that can inhibit viral infection by targeting various components of this virus which are essential in spreading the infection and replication mechanism. The repurposing of the drug against coronavirus has become a lot easier and efficient with the advancement in these computational techniques. Hence, this review covers the recent developments in the virtual screening of potentially hit compounds against COVID-19.

13.
Top Curr Chem (Cham) ; 379(6): 41, 2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1469799

ABSTRACT

Sustainable scientific software needs a strong collaboration framework to ensure continuity by passing on the tools, skills and knowledge needed to the next generation. The COVID-19 pandemic triggered the unexpected effect of accelerating the development of remote platforms and tools to open up collaborations to a wider global community. In this article we outline the elements needed for such a framework, such as education, tools and community building, and discuss the current advances in technology with a nod to the future.


Subject(s)
COVID-19 , Pandemics , Humans , SARS-CoV-2 , Technology
14.
ChemistrySelect ; 6(29): 7429-7435, 2021 Aug 06.
Article in English | MEDLINE | ID: covidwho-1353599

ABSTRACT

The earth has witnessed the greatest global health crisis due to the outbreak of the SARS-CoV-2 virus in late 2019, resulting in the pandemic COVID-19 with 3.38 million mortality and 163 million infections across 222 nations. Therefore, there is an urgent need for an effective therapeutic option against the SARS-CoV-2 virus. Transition metal complexes with unique chemical, kinetic and thermodynamic properties have recently emerged as the viable alternative for medicinal applications. Herein, the potential application of selected antiviral transition metal-based compounds against the SARS-CoV-2 virus was explored in silico. Initially, the transition metal-based antiviral compounds (1-5) were identified based on the structural similarity of the viral proteins (proteases, reverse transcriptase, envelop glycoproteins, etc.) of HIV, HCV, or Influenza virus with the proteins (S-protein, RNA-dependent RNA polymerase, proteases, etc) of SARS-CoV-2 virus. Hence the complexes (1-5) were subjected to ADME analysis for toxicology and pharmacokinetics report and further for the molecular docking calculations, selectively with the viral proteins of the SARS-CoV-2 virus. The molecular docking studies revealed that the iron-porphyrin complex (1) and antimalarial drug, ferroquine (2) could be the potential inhibitors of Main protease (Mpro) and spike proteins respectively of SARS-CoV-2 virus. The complex 1 exhibited high binding energy of -11.74 kcal/mol with the Mpro of SARS-CoV-2. Similarly ferroquine exhibitred binding energy of -7.43 kcal/mol against spike protein of SARS-CoV-2. The complex 5 also exhibited good binding constants values of -7.67, -8.68 and -7.82 kcal/mol with the spike protein, Mpro and RNA dependent RNA polymerase (RdRp) proteins respectively. Overall, transition metal complexes could provide an alternative and viable therapeutic solution for COVID-19.

15.
Curr Med Chem ; 28(40): 8333-8383, 2021.
Article in English | MEDLINE | ID: covidwho-1269946

ABSTRACT

The recent pandemic due to SARS-CoV-2, the last isolated human betacoronavirus, has revolutionized modern knowledge of the pathogenesis of viral pneumonia. The lack of specific antiviral drugs and the need to develop adequate research for new antiviral drugs capable of treating this new form of the disease undertook three different research paths quickly. The first one is aimed to test antiviral molecules already present in therapeutic use, with a mechanism of action directed towards viral proteins functional to replication or adsorption; the second one, it is the repositioning of molecules with known pharmacological activity for which various chemistry studies have been prepared in an attempt to find new and specific viral targets; the third, it is the search for molecules of natural origin for which to demonstrate a specific anti-coronavirus activity. Many databases of natural and synthetic substances have been used for the identification of potent inhibitors of various viral targets. The field of computer-aided drug design seems to be promising and useful for the identification of SARS-CoV-2 inhibitors; hence, different structure- and ligand- based computational approaches have been used for their identification. This review analyzes in-depth and critically the most recent publications in the field of applied computational chemistry to find out molecules of natural origin with potent antiviral activity. Furthermore, a critical and functional selection of some molecules with the best hypothetical anti-SARS-CoV-2 activity is made for further studies by biological tests.


Subject(s)
COVID-19 , Pneumonia, Viral , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Fertilization , Humans , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2
16.
ChemMedChem ; 16(2): 340-354, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-1044678

ABSTRACT

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro ) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro . Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Isoindoles/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Benzamides/chemical synthesis , Benzamides/metabolism , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/metabolism , Isoindoles/chemical synthesis , Isoindoles/metabolism , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effects
17.
Heliyon ; 6(11): e05558, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-938952

ABSTRACT

The emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed a greater challenge for the world. Coronavirus has infected over 38.3 million people and caused millions of deaths worldwide. The COVID-19 outbreak has accentuated the need for additional efforts to develop broad-spectrum therapeutics to combat SARS-CoV-2 infection. In the current investigation, an attempt was made to design potential SARS-CoV PLpro inhibitors containing naphthalene and 3,4-dihydro-2H-pyran moieties connected via -NHCO- linker. The ligands obeyed Lipinski's rule and were found to have good drug-likeness and ADMET properties. Docking simulations confirmed strong binding affinity and inhibition potential of the designed ligands against the receptor SARS CoV-2 Papain-like protease (PLpro). LigandL10 incorporating the oxadiazole ring system displayed better binding affinity than the control 5-acetamido-2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide. Further, the docked complex of LigandL10 was subjected to molecular dynamics (MD) simulation to examine the molecular mechanisms of protein-ligand interactions. The results of the present study are encouraging. Ligand L10 emerged as the most potent ligand in the series and could be considered for further research for the development of potential therapeutics for the treatment of COVID-19.

18.
Heliyon ; 6(11): e05544, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-938951

ABSTRACT

The disease called severe acute respiratory syndrome (SARS) is a lifestyle intimidating viral contamination affected by a positive, single stranded novel RNA virus (COVID-2019) from the enveloped coronaviruse family. The COVID-2019 virus has affected many people, scattering promptly, and researchers are attempting to find out medicines for its effectual cure in all over the globe. Chloroquine (ChQ) and its derivatives, an older drug used for the cure of malaria, is exposed to encompass a perceptible feasibility and commendable well-being in opposition to SARS CoV-2 associated pneumonia clinical trials conducted in China. Later on, a few investigations have been directed to find and present SARS CoV-2 antiviral medications. The aim of this present work deals with the potential binding interactions of some imidazolium salts with Nsp9 (Nonstructural protein 9) RNA binding protein of SARS CoV-2.

19.
ChemMedChem ; 16(2): 340-354, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-878190

ABSTRACT

Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro ) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro . Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Isoindoles/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Benzamides/chemical synthesis , Benzamides/metabolism , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/metabolism , Isoindoles/chemical synthesis , Isoindoles/metabolism , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effects
20.
Chemistry ; 26(51): 11782-11795, 2020 Sep 10.
Article in English | MEDLINE | ID: covidwho-777429

ABSTRACT

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C1 -O-octyloxy glycans, α/ß-glucoside (α/ß-Glc), α/ß-mannoside (α/ß-Man), and ß-galactoside (ß-Gal), was studied by mass spectrometry, 1 H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to ß-Glc. SCR019 (3-indole) binds only to ß-Man. SCR020 (2-pyridine) binds ß-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and ß-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host-guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR, where the former are driven by positive allosteric cooperativity induced by glycan-glycan contacts.


Subject(s)
Carbohydrates/chemical synthesis , Lectins, C-Type/chemistry , Mannose-Binding Lectins/chemistry , Mannose/chemical synthesis , Polysaccharides/chemistry , Receptors, Artificial/chemistry , Receptors, Cell Surface/chemistry , Carbohydrates/chemistry , Magnetic Resonance Spectroscopy , Mannose/chemistry , Models, Molecular , Molecular Structure
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