A New Proposed Mechanism of some Known Drugs Targeting the SARS-CoV-2 Spike Glycoprotein Using Molecular Docking

COVID-19 is caused by the novel enveloped beta-coronavirus with a genomic RNA closely related to severe acute respiratory syndrome-corona virus (SARS-CoV) and is named coronavirus 2 (SARS-CoV-2). In this study, six synthetic drugs were specifically docked against the RBD. Most of the six compounds were observed to fit nicely with specific noncovalent interactions. Oseltamivir was found to be the most strongly interacting with the RBD, exhibiting high values of full fitness and low free energy of binding. It formed multiple noncovalent bonds in the region of the active site. Hydroxychloroquine also demonstrated high binding affinity in the solvent accessibility state and fit nicely into the S-protein's active pocket. The results revealed that these compounds could be potent inhibitors of S-protein that could, to some extent, block its interaction with ACE-2. It is obvious from the 3D structure of SARS-CoV-2 spike protein was changed with the interaction of different drugs, which led to the unsuitability to bind ACE2 receptor. Hence, laboratory studies elucidating the action of these compounds on SARS-CoV-2 are warranted for clinical assessments. Chloroquine, hydroxychloroquine, and oseltamivir interacted well with the receptor-binding domain of S-protein via noncovalent interactions and were recommended as excellent candidates for COVID-19.

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A new proposed mechanism of some known drugs targeting the SARS-CoV-2 spike glycoprotein using molecular docking

10.21203/rs.3.rs-105677/v1 ◽

2020 ◽

Author(s):

Tarek Moussa ◽

Nevien Sabry

Keyword(s):

Receptor Binding ◽

Protein Interactions ◽

Viral Entry ◽

Noncovalent Interactions ◽

3D Structure ◽

Binding Domain ◽

Receptor Binding Domain ◽

S Protein ◽

Noncovalent Bonds ◽

Free Energy Of Binding

Abstract COVID-19 is caused by the novel enveloped beta-coronavirus with a genomic RNA closely related to severe acute respiratory syndrome-corona virus (SARS-CoV) and is named coronavirus 2 (SARS-CoV-2). The receptor binding domain (RBD) of the S-protein interacts with the human ACE-2 receptor that enables the initiation of viral entry. Hence, blocking the S-protein interactions by means of synthetic compounds mark the pivotal step for targeting SARS-CoV-2. Most of the six compounds were observed to fit nicely with specific noncovalent interactions, including H bonds, electrostatic, Van der Waals and hydrophobic bonds (pi and sigma bonds). Oseltamivir was found to be the most strongly interacting with the RBD, exhibiting high values of full fitness and low free energy of binding. it formed multiple noncovalent bonds in the region of the active site. Hydroxychloroquine also demonstrated high binding affinity in the solvent accessbility state and fit nicely into the active pocket of the S-protein. The results revealed that these compounds could be potent inhibitors of S-protein that could, to some extent, block its interaction with ACE-2. It is obvious from the 3D structure of SARS-CoV-2 spike protein was changed with the interaction of different drugs, which led to the unsuitability to bind ACE2 receptor. Hence, laboratory studies elucidating the action of these compounds on SARS-CoV-2 are warranted for clinical assessments. Chloroquine, hydroxychloroquine and oseltamivir interacted well with the receptor binding domain of S-protein via noncovalent interactions and recommended as excellent candidates for COVID-19.

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Synthetic and semi-synthetic drugs as promising therapeutic option for the treatment of COVID-19

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201204162103 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ekta Shirbhate ◽

Preeti Patel ◽

Vijay K Patel ◽

Ravichandran Veerasamy ◽

Prabodh C Sharma ◽

...

Keyword(s):

Therapeutic Option ◽

Antiviral Treatment ◽

The Novel ◽

Clinical Experiences ◽

Synthetic Compounds ◽

Synthetic Drugs ◽

Global Pandemic ◽

The World ◽

Novel Coronavirus

: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.

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Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2)

10.21203/rs.3.rs-29037/v2 ◽

2020 ◽

Author(s):

Xingyi Guo ◽

Zhishan Chen ◽

Yumin Xia ◽

Weiqiang Lin ◽

Hongzhi Li

Keyword(s):

Genetic Variation ◽

The Novel ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Missense Variants ◽

Catalytic Metal ◽

Using Data ◽

Novel Coronavirus ◽

Insight Into

Abstract Background: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. Methods: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program.Results: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian.Conclusions: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.

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Noncovalent Bonds, Spectral and Thermal Properties of Substituted Thiazolo[2,3-b][1,3]thiazinium Triiodides

Crystals ◽

10.3390/cryst9100506 ◽

2019 ◽

Vol 9 (10) ◽

pp. 506 ◽

Cited By ~ 6

Author(s):

Irina Yushina ◽

Natalya Tarasova ◽

Dmitry Kim ◽

Vladimir Sharutin ◽

Ekaterina Bartashevich

Keyword(s):

Electron Density ◽

Noncovalent Interactions ◽

Material Design ◽

Spectroscopic Properties ◽

Structural Features ◽

Halogen Bonds ◽

X Ray Diffraction ◽

Raman Spectroscopic ◽

Pairwise Interactions ◽

Noncovalent Bonds

The interrelation between noncovalent bonds and physicochemical properties is in the spotlight due to the practical aspects in the field of crystalline material design. Such study requires a number of similar substances in order to reveal the effect of structural features on observed properties. For this reason, we analyzed a series of three substituted thiazolo[2,3-b][1,3]thiazinium triiodides synthesized by an iodocyclization reaction. They have been characterized with the use of X-ray diffraction, Raman spectroscopy, and thermal analysis. Various types of noncovalent interactions have been considered, and an S…I chalcogen bond type has been confirmed using the electronic criterion based on the calculated electron density and electrostatic potential. The involvement of triiodide anions in the I…I halogen and S…I chalcogen bonding is reflected in the Raman spectroscopic properties of the I–I bonds: identical bond lengths demonstrate different wave numbers of symmetric triiodide vibration and different values of electron density at bond critical points. Chalcogen and halogen bonds formed by the terminal iodine atom of triiodide anion and numerous cation…cation pairwise interactions can serve as one of the reasons for increased thermal stability and retention of iodine in the melt under heating.

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Pillararenes Trimer for Self-Assembly

Nanomaterials ◽

10.3390/nano10040651 ◽

2020 ◽

Vol 10 (4) ◽

pp. 651 ◽

Cited By ~ 3

Author(s):

Huacheng Zhang ◽

Zhaona Liu ◽

Hui Fu

Keyword(s):

Self Assembly ◽

Driving Forces ◽

Click Reaction ◽

Noncovalent Interactions ◽

Coupling Reaction ◽

Covalent Bonds ◽

Guest Molecules ◽

Palladium Catalyzed ◽

Noncovalent Bonds ◽

External Stimuli

Pillararenes trimer with particularly designed structural geometry and excellent capacity of recognizing guest molecules is a very efficient and attractive building block for the fabrication of advanced self-assembled materials. Pillararenes trimers could be prepared via both covalent and noncovalent bonds. The classic organic synthesis reactions such as click reaction, palladium-catalyzed coupling reaction, amidation, esterification, and aminolysis are employed to build covalent bonds and integrate three pieces of pillararenes subunits together into the “star-shaped” trimers and linear foldamers. Alternatively, pillararenes trimers could also be assembled in the form of host-guest inclusions and mechanically interlocked molecules via noncovalent interactions, and during those procedures, pillararenes units contribute the cavity for recognizing guest molecules and act as a “wheel” subunit, respectively. By fully utilizing the driving forces such as host-guest interactions, charge transfer, hydrophobic, hydrogen bonding, and C–H…π and π–π stacking interactions, pillararenes trimers-based supramolecular self-assemblies provide a possibility in the construction of multi-dimensional materials such as vesicular and tubular aggregates, layered networks, as well as frameworks. Interestingly, those assembled materials exhibit interesting external stimuli responsiveness to e.g., variable concentrations, changed pH values, different temperature, as well as the addition/removal of competition guests and ions. Thus, they could further be used for diverse applications such as detection, sorption, and separation of significant multi-analytes including metal cations, anions, and amino acids.

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The supramolecular structure of a cadmium complex with the new functionalized terpyridine ligand 4′-[4-(pyrimidin-5-yl)phenyl]-2,2′:6′,2′′-terpyridine (L1): aqua(L1-κ3N,N′,N′′)(nitrato-κ2O,O′)(nitrato-κO)cadmium(II) dihydrate

Acta Crystallographica Section C Crystal Structure Communications ◽

10.1107/s0108270113017356 ◽

2013 ◽

Vol 69 (8) ◽

pp. 822-825 ◽

Cited By ~ 2

Author(s):

Juan Granifo ◽

Rubén Gaviño ◽

Eleonora Freire ◽

Ricardo Baggio

Keyword(s):

Title Compound ◽

Noncovalent Interactions ◽

Pentagonal Bipyramid ◽

Planar Geometry ◽

Cadmium Complex ◽

The Novel ◽

Monodentate Ligands ◽

Nitrate Anions ◽

Packing Effects ◽

Chelating Groups

The monomeric title compound, aqua(nitrato-κ2O,O′)(nitrato-κO){4′-[4-(pyrimidin-5-yl)phenyl]-2,2′:6′,2′′-terpyridine-κ3N,N′,N′′}cadmium(II) dihydrate, [Cd(NO3)2(C25H17N5)(H2O)]·2H2O, consists of a seven-coordinated CdIIcentre bound to the novel 4′-[4-(pyrimidin-5-yl)phenyl]-2,2′:6′,2′′-terpyridine (L1) ligand (behaving as a tridentate chelate), two nitrate anions (as chelating–bidentate and monodentate ligands) and a water O atom. Both chelating groups define the base of a slightly deformed pentagonal bipyramid, while the monocoordinated ligands occupy the apices. The four heterocycles inL1 form a planar skeleton, while the central benzene ring is rotated from this planar geometry by more than 30°, probably because of packing effects. Noncovalent interactions lead to the formation of columnar arrays parallel to [100].

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The Second Extracellular Loop of CCR5 Contains the Dominant Epitopes for Highly Potent Anti-Human Immunodeficiency Virus Monoclonal Antibodies

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01302-06 ◽

2007 ◽

Vol 51 (4) ◽

pp. 1386-1397 ◽

Cited By ~ 16

Author(s):

Jun Zhang ◽

Eileen Rao ◽

Marianna Dioszegi ◽

Rama Kondru ◽

Andre DeRosier ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Homology Model ◽

The Novel ◽

Extracellular Loop ◽

Linear Peptide ◽

Immunodeficiency Virus ◽

Antiviral Activities ◽

Multiple Species ◽

Loop 2 ◽

High Binding Affinity

ABSTRACT Six mouse anti-human CCR5 monoclonal antibodies (mAbs) that showed potent antiviral activities were identified from over 26,000 mouse hybridomas. The epitopes for these mAbs were determined by using various CCR5 mutants, including CCR5/CCR2B chimeras. One mAb, ROAb13, was found to bind to a linear epitope in the N terminus of CCR5. Strikingly, the other five mAbs bind to epitopes derived from extracellular loop 2 (ECL2). The three most potent mAbs, ROAb12, ROAb14, and ROAb18, require residues from both the N-terminal (Lys171 and Glu172) and C-terminal (Trp190) halves of ECL2 for binding; two other mAbs, ROAb10 and ROAb51, which also showed potent antiviral activities, require Lys171 and Glu172 but not Trp190 for binding. Binding of the control mAb 2D7 completely relies on Lys171 and Glu172. Unlike 2D7, the novel mAbs ROAb12, ROAb14, and ROAb18 do not bind to the linear peptide 2D7-2SK. In addition, all three mAbs bind to monkey CCR5 (with Arg at position 171 instead of Lys); however, 2D7 does not. Since five of the six most potent CCR5 mAbs derived from the same pool of immunized mice require ECL2 as epitopes, we hypothesize that CCR5 ECL2 contains the dominant epitopes for mAbs with potent antiviral activities. These dominant epitopes were found in CCR5 from multiple species and were detected in large proportions of the total cell surface CCR5. mAbs recognizing these epitopes also showed high binding affinity. A homology model of CCR5 was generated to aid in the interpretation of these dominant epitopes in ECL2.

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Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

10.26434/chemrxiv.11871402.v3 ◽

2020 ◽

Cited By ~ 13

Author(s):

Micholas Smith ◽

Jeremy C. Smith

Keyword(s):

Small Molecules ◽

High Throughput Screening ◽

Protein S ◽

Host Cells ◽

Spike Protein ◽

The Novel ◽

S Protein ◽

Host Virus Interactions ◽

Virus Interactions ◽

Ranked List

The novel Wuhan coronavirus (SARS-CoV-2) has been sequenced, and the virus shares substantial similarity with SARS-CoV. Here, using a computational model of the spike protein (S-protein) of SARS-CoV-2 interacting with the human ACE2 receptor, we make use of the world's most powerful supercomputer, SUMMIT, to enact an ensemble docking virtual high-throughput screening campaign and identify small-molecules which bind to either the isolated Viral S-protein at its host receptor region or to the S protein-human ACE2 interface. We hypothesize the identified small-molecules may be repurposed to limit viral recognition of host cells and/or disrupt host-virus interactions. A ranked list of compounds is given that can be tested experimentally.<br>

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Digital phenotyping of complex psychological responses to the COVID-19 pandemic (Preprint)

10.2196/preprints.26190 ◽

2020 ◽

Author(s):

Thomas D. Hull ◽

Jacob Levine ◽

Niels Bantilan ◽

Angel N. Desai ◽

Maimuna S. Majumder

Keyword(s):

Mental Health ◽

Language Processing ◽

Anxiety Symptoms ◽

Depression Symptoms ◽

The Novel ◽

Depression And Anxiety ◽

Clinical Assessments ◽

Digital Phenotyping ◽

Novel Coronavirus ◽

Therapy Service

BACKGROUND The novel coronavirus disease 2019 (COVID-19) has negatively impacted mortality, economic conditions, and mental health and these impacts are likely to continue after the pandemic comes to an end. OBJECTIVE At present, no method has characterized the mental health burden of the pandemic distinct from pre-COVID-19 levels. Accurate detection of illness is critical to facilitate pandemic-related treatment to prevent worsening symptoms. METHODS An algorithm for the isolation of pandemic-related concerns on a large digital mental health service is reported that utilized natural language processing (NLP) on unstructured therapy transcript data, in parallel with brief clinical assessments of depression and anxiety symptoms. RESULTS Results demonstrate a significant increase in COVID-related intake anxiety symptoms, but no detectable difference in intake depression symptoms. Transcript analyses identified terms classifiable into 24 symptoms in excess of those included in the diagnostic criteria for anxiety and depression. CONCLUSIONS Findings for this large digital therapy service suggest that treatment seekers are presenting with more severe intake anxiety levels than before the COVID-19 outbreak. Importantly, monitoring additional symptoms as part of a new COVID-19 Syndrome category could be advised to fully capture the effects of COVID019 on mental health.

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Pillararenes Trimer for Self-Assembly

10.32545/encyclopedia202004.0005.v2 ◽

2020 ◽

Author(s):

Huacheng Zhang

Keyword(s):

Self Assembly ◽

Driving Forces ◽

Click Reaction ◽

Noncovalent Interactions ◽

Coupling Reaction ◽

Covalent Bonds ◽

Guest Molecules ◽

Palladium Catalyzed ◽

Noncovalent Bonds ◽

External Stimuli

Pillararenes trimer with particularly designed structural geometry and excellent capacity of recognizing guest molecules is a very efficient and attractive building block for the fabrication of advanced self-assembled materials. Pillararenes trimers could be prepared via both covalent and noncovalent bonds. The classic organic synthesis reactions such as click reaction, Palladium-catalyzed coupling reaction, amidation, esterification and aminolysis are employed to build covalent bonds and integrate three pieces of pillararenes subunits together into the “star-shaped” trimers and linear foldamers. Alternatively, pillararenes trimers could also be assembled in the form of host-guest inclusions and mechanically interlocked molecules via noncovalent interactions, and during those procedures, pillararenes units contribute the cavity for recognizing guest molecules and act as a “wheel” subunit, respectively. By fully utilizing the driving forces such as host-guest interactions, charge transfer, hydrophobic, hydrogen bonding, C—H…π and π—π stacking interactions, pillararenes trimers-based supramolecular self-assemblies provide a possibility in the construction of multi-dimensional materials such as vesicular and tubular aggregates, layered networks, as well as frameworks. Interestingly, those assembled materials exhibit interesting external stimuli responsiveness to e.g., variable concentrations, changed pH values, different temperature, as well as the addition/removal of competition guests and ions. Thus, they could further be used for diverse applications such as detection, sorption and separation of significant multi-analytes including metal cations, anions and amino acids.

Download Full-text