Thermodynamics and kinetics in antibody resistance of the 501Y.V2 SARS-CoV-2 variant

Understanding the thermodynamics and kinetics of the binding process of an antibody to the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein is very important for the development of COVID-19 vaccines. In particular, it is essential to understand how the binding mechanism may change under the effects of RBD mutations. In this context, we have demonstrated that the South African variant (B1.351 or 501Y.V2) can resist the neutralizing antibody (NAb). Three substitutions in the RBD including K417N, E484K, and N501Y alter the free energy landscape, binding pose, binding free energy, binding kinetics, hydrogen bonding, nonbonded contacts, and unbinding pathway of RBD + NAb complexes. The low binding affinity of NAb to 501Y.V2 RBD confirms the antibody resistance of the South African variant. Moreover, the fragment of NAb + RBD can be used as an affordable model to investigate changes in the binding process between the mutated RBD and antibodies.

Increasing FEL minima of 501Y.V2 RBD + antibody in comparison with the WT RBD systems imply that the complex 501Y.V2 RBD + antibody is more unstable than the WT one.     

Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (−)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (K_D) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world.     

Single point mutations can potentially enhance infectivity of SARS-CoV-2 revealed by in silico affinity maturation and SPR assay

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates viral cell attachment and serves as a promising target for therapeutics development. Mutations on the S-RBD may alter its affinity to the cell receptor and affect the potency of vaccines and antibodies. Here we used an in silico approach to predict how mutations on RBD affect its binding affinity to hACE2 (human angiotensin-converting enzyme2). The effect of all single point mutations on the interface was predicted. SPR assay results show that 6 out of 9 selected mutations can strengthen binding affinity. Our prediction has reasonable agreement with the previous deep mutational scan results and recently reported mutants. Our work demonstrated the in silico method as a powerful tool to forecast more powerful virus mutants, which will significantly benefit the development of broadly neutralizing vaccine and antibody.

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates viral cell attachment and serves as a promising target for therapeutics development.     

Insight into the origin of SARS-CoV-2 through structural analysis of receptor recognition: a molecular simulation study

Bats and pangolins are considered to be potential hosts of the new coronavirus SARS-CoV-2, based on its genome similarity to coronaviruses of these species (Bat-CoV-RaTG13 and Pangolin-CoV). The receptor-binding domain (RBD), a functional component of the spike protein, is responsible for binding of SARS-CoV-2 by human ACE2 receptors and is also key to cross-species viral transmission. We performed molecular dynamics (MD) simulations using structures of hACE2 in complex with the RBD of SARS-CoV-2, SARS-CoV, Pangolin-CoV and Bat-CoV-RaTG13, respectively. By analyzing the hydrogen-bonding network at the RBD–hACE2 interface and estimating the binding free energies between RBD and hACE2, we found Pangolin-CoV bound hACE2 in a similar state as did SARS-CoV-2, and both of them bound hACE2 more strongly than did Bat-CoV-RaTG13 or SARS-CoV. We further identified two major adaptation mutations of SARS-CoV-2-RBD, which may have significant roles in regulating the recognition and binding between RBD and hACE2. Our results add to existing evidence that Pangolins have the potential to act as an intermediate host for SARS-CoV-2, and provide guidance for future design of antiviral drugs and vaccines.

The origin of SARS-CoV-2 through structural analysis of receptor recognition was investigated by molecular dynamics simulations.     

Newly designed analogues from SARS-CoV inhibitors mimicking the druggable properties against SARS-CoV-2 and its novel variants

The emerging variants of SARS coronavirus-2 (SARS-CoV-2) have been continuously spreading all over the world and have raised global health concerns. The B.1.1.7 (United Kingdom), P.1 (Brazil), B.1.351 (South Africa) and B.1.617 (India) variants, resulting from multiple mutations in the spike glycoprotein (SGp), are resistant to neutralizing antibodies and enable increased transmission. Hence, new drugs might be of great importance against the novel variants of SARS-CoV-2. The SGp and main protease (M^pro) of SARS-CoV-2 are important targets for designing and developing antiviral compounds for new drug discovery. In this study, we selected seventeen phytochemicals and later performed molecular docking to determine the binding interactions of the compounds with the two receptors and calculated several drug-likeliness properties for each compound. Luteolin, myricetin and quercetin demonstrated higher affinity for both the proteins and interacted efficiently. To obtain compounds with better properties, we designed three analogues from these compounds and showed their greater druggable properties compared to the parent compounds. Furthermore, we found that the analogues bind to the residues of both proteins, including the recently identified novel variants of SARS-CoV-2. The binding study was further verified by molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) approaches by assessing the stability of the complexes. MD simulations revealed that Arg457 of SGp and Met49 of M^pro are the most important residues that interacted with the designed inhibitors. Our analysis may provide some breakthroughs to develop new therapeutics to treat the proliferation of SARS-CoV-2 in vitro and in vivo.

Three designed inhibitors with potential inhibition efficacy against the emerging variants of SARS coronavirus-2 (SARS-CoV-2).     

Interaction analyses of SARS-CoV-2 spike protein based on fragment molecular orbital calculations

At the stage of SARS-CoV-2 infection in human cells, the spike protein consisting of three chains, A, B, and C, with a total of 3300 residues plays a key role, and thus its structural properties and the binding nature of receptor proteins to host human cells or neutralizing antibodies has attracted considerable interest. Here, we report on interaction analyses of the spike protein in both closed (PDB-ID: 6VXX) and open (6VYB) structures, based on large-scale fragment molecular orbital (FMO) calculations at the level of up to the fourth-order Møller–Plesset perturbation with singles, doubles, and quadruples (MP4(SDQ)). Inter-chain interaction energies were evaluated for both structures, and a mutual comparison indicated considerable losses of stabilization energies in the open structure, especially in the receptor binding domain (RBD) of chain-B. The role of charged residues in inter-chain interactions was illuminated as well. By two separate calculations for the RBD complexes with angiotensin-converting enzyme 2 (ACE2) (6M0J) and B38 Fab antibody (7BZ5), it was found that the binding with ACE2 or antibody partially compensated for this stabilization loss of RBD.

Visualized IFIE results seen from chain-B of spike protein.     

In silico design of peptides with binding to the receptor binding domain (RBD) of the SARS-CoV-2 and their utility in bio-sensor development for SARS-CoV-2 detection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people across the globe and created not only a health emergency but also a financial crisis. This virus attacks the angiotensin-converting enzyme 2 (ACE2) receptor situated on the surface of the host cell membrane. The spike protein of the virus binds to this receptor which is a critical step in infection. A molecule which can specifically stop this binding could be a potential therapeutic agent. In this study, we have tested 12 potential peptides which can bind to the receptor binding domain (RBD) of the spike protein of the virus and thus can potentially inhibit the binding of the latter on ACE2 receptors. These peptides are screened based on their binding with the RBD of the spike protein and aqueous stability, obtained using several atomistic molecular dynamic simulations. The potential of mean force calculation of peptides confirmed their binding to the RBD of the spike protein. Furthermore, two potential peptides were tested for use in a biosensing application for SARS-CoV-2 detection. Two types of biosensing platforms, a graphene sheet and a carbon nano tube (CNT) were tested. The peptides were modified in order to functionalize the graphene and CNT. Based on the interaction between the substrate, peptide and spike protein, the utility of the screened peptide for a given bio sensing platform is discussed and recommended.

The protocol for peptide design and testing for its usage as a sensor.     

CeO2@NH2 functionalized electrodes for the rapid detection of SARS-CoV-2 spike receptor binding domain

A detection method based on an electrochemical aptasensor has been developed as an alternative fast, portable, simple, inexpensive, and high-accuracy detection method for detecting the SARS-CoV-2 Spike Receptor Binding Domain (spike RBD). The CeO₂@NH₂ functionalized Screen Printed Carbon Electrode (SPCE) was used to immobilize an aminated aptamer of spike RBD protein via glutaraldehyde as a linker. The aptamer''s interaction with the SARS-CoV-2 Spike RBD was measured via the [Fe(CN)₆]^4−/3− redox system signal. Experimental conditions were optimized using a Box–Behnken experimental design and showed that the optimal conditions of the SARS-CoV-2 aptasensor were 1.5 ng mL⁻¹ of aptamer, immobilization of aptamer for 60 minutes, and Spike RBD incubation for 10 minutes. The developed aptasensor was able to detect the standard SARS-CoV-2 Spike RBD with a detection limit of 0.017 ng mL⁻¹ in the range of 0.001–100 ng mL⁻¹. This aptasensor was used to detect salivary and oropharyngeal swab samples of normal individuals with the addition of Spike RBD, and the recoveries were 92.96% and 96.52%, respectively. The testing on nasopharyngeal swab samples of COVID-19 patients showed that the aptasensor results were comparable with the qRT-PCR results. Thus, the developed aptasensor has the potential to be applied as a SARS-CoV-2 rapid test method for clinical samples.

A detection method based on an electrochemical aptasensor has been developed as an alternative fast, portable, simple, inexpensive, and high-accuracy detection method for detecting the SARS-CoV-2 Spike Receptor Binding Domain (spike RBD).     

Curcumin to inhibit binding of spike glycoprotein to ACE2 receptors: computational modelling,simulations, and ADMET studies to explore curcuminoids against novel SARS-CoV-2 targets

The recent emergence of the novel coronavirus (SARS-CoV-2) has raised global concern as it is declared a pandemic by the WHO. However, to date, there is no current regimen to mitigate the molecular pathogenesis of SARS-CoV-2 virus. Curcuminoids, bioactive ingredients present in Curcuma longa (turmeric), are known to exhibit diverse pharmacological properties. To the best of our understanding to date, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for the host cellular entry. This is mediated via proteins of SARS-CoV-2, especially the spike glycoprotein receptor binding domain. Accordingly, our primary objective is to thwart virus replication and binding to the host system, leading us to probe curcuminoids efficiency towards key surface drug target proteins using the computational biology paradigm approach. Specifically, fourteen natural curcuminoids were studied for their possibility of inhibiting SARS-CoV-2. We studied their in silico properties towards SARS-CoV-2 target proteins by homology modelling, ADME, drug-likeness, toxicity predictions, docking molecular dynamics simulations and MM-PBSA free energy estimation. Among the curcuminoids docked to the receptor binding domain of SARS-CoV-2 spike glycoprotein, the keto and enol forms of curcumin form strong hydrogen bond interactions with ACE2 binding residues Q493, T501, Y505, Y489 and Q498. Molecular dynamics simulations, free energy binding and interaction energy validated the interaction and stability of the docked keto and enol forms of curcumin.

The significant role of curcumin against SARS-CoV-2 drug targets to thwart virus replication and binding into the host system using the computational biology paradigm approach.     

A phytochemical-based medication search for the SARS-CoV-2 infection by molecular docking models towards spike glycoproteins and main proteases

Identifying best bioactive phytochemicals from different medicinal plants using molecular docking techniques demonstrates a potential pre-clinical compound discovery against SARS-CoV-2 viral infection. The in silico screening of bioactive phytochemicals with the two druggable targets of SARS-CoV-2 by simple precision/extra precision molecular docking methods was used to compute binding affinity at its active sites. phyllaemblicin and cinnamtannin class of phytocompounds showed a better binding affinity range (−9.0 to −8.0 kcal mol⁻¹) towards both these SARS-CoV-2 targets; the corresponding active site residues in the spike protein were predicted as: Y453, Q496, Q498, N501, Y449, Q493, G496, T500, Y505, L455, Q493, and K417; and M^pro: Q189, H164, H163, P168, H41, L167, Q192, M165, C145, Y54, M49, and Q189. Molecular dynamics simulation further established the structural and energetic stability of protein–phytocompound complexes and their interactions with their key residues supporting the molecular docking analysis. Protein–protein docking using ZDOCK and Prodigy server predicted the binding pose and affinity (−13.8 kcal mol⁻¹) of the spike glycoprotein towards the human ACE2 enzyme and also showed significant structural variations in the ACE2 recognition site upon the binding of phyllaemblicin C compound at their binding interface. The phyllaemblicin and cinnamtannin class of phytochemicals can be potential inhibitors of both the spike and M^pro proteins of SARS-CoV-2; furthermore, its pharmacology and clinical optimization would lead towards novel COVID-19 small-molecule therapy.

Identifying best bioactive phytochemicals from different medicinal plants using molecular docking techniques demonstrates a potential pre-clinical compound discovery against SARS-CoV-2 viral infection.     

Carbon nanotubes for rapid capturing of SARS-COV-2 virus: revealing a mechanistic aspect of binding based on computational studies

We investigate the binding interactions of synthesized multi-walled carbon nanotubes (MWCNTs) with SARS-CoV-2 virus. Two essential components of the SARS-CoV-2 structure i.e.6LU7 (main protease of SARS-CoV-2) and 6LZG (spike receptor-binding domain complexed with its receptor ACE2) were used for computational studies. MWCNTs of different morphologies (zigzag, armchair and chiral) were synthesized through a thermal chemical vapour deposition process as a function of pyrolysis temperature. A direct correlation between radius to volume ratio of the synthesized MWCNTs and the binding energies for all three (zigzag, armchair and chiral) conformations were observed in our computational studies. Our result suggests that MWCNTs interact with the active sites of the main protease along with the host angiotensin-converting enzyme2 (ACE2) receptors. Furthermore, it is also observed that MWCNTs have significant binding affinities towards SARS-CoV-2. However, the highest free binding energy of −87.09 kcal mol⁻¹ with 6LZG were shown by the armchair MWCNTs with SARS-CoV-2 through the simulated molecular dynamic trajectories, which could alter the SARS-CoV-2 structure with higher accuracy. The radial distribution function also confirms the density variation as a function of distance from a reference particle of MWCNTs for the study of interparticle interactions of the MWCNT and SARS-CoV-2. Due to these interesting attributes, such MWCNTs could find potential application in personal protective equipment (PPE) and diagnostic kits.

Investigation of the binding interactions of synthesized multi-walled carbon nanotubes (MWCNTs) with SARS-CoV-2 virus.     

Understanding the role of galectin inhibitors as potential candidates for SARS-CoV-2 spike protein: in silico studies

The Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has been rapidly transmitting and leaving its footprints across the globe. Stringent measures like complete lockdown and extensive testing have been employed by many countries to slow it down in its tracks until a viable treatment is found. Therefore, in the current scenario, prompt solutions need to be uncovered to tackle the virus. In the present study, 330 galectin inhibitors were tested against SARS-CoV-2 spike (S) protein with the aid of molecular docking and molecular dynamics. Finally, the binding free energy and contributing energies were calculated for 2 top scoring ligands by using MM–GBSA method. Many of the galectin inhibitors displayed high binding score against the S protein. They were found to bind to the site of contact of S protein to ACE2. Thus, they show promise of disrupting the ACE2–S protein binding and prevent the virus from invading the host cell. Among the ligands screened, TD-139, a molecule currently in Phase IIb clinical trials, was found to be a potential hit. The present study paves the way for in vitro and in vivo testing of galectin inhibitors against SARS-CoV-2. In addition, it warrants a swift examination of TD-139 for treating COVID-19.

Galectin 3 have the potential to inhibit the SARS-CoV-2 spike protein. We validated the studies by docking, MD and MM/GBSA calculations.     

Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase

According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting 250+ M people. Despite the current vaccination momentum, thousands of people die every day by COVID-19. Suggesting possible blockers of the viral RNA-dependent RNA polymerase is highly needed for potential effective therapeutics against SARS-CoV-2. This study utilizes combined molecular dynamics simulation and molecular docking to test novel guanosine derivatives against SARS-CoV-2 RdRp. Results reveal the binding potency of nineteen guanosine derivatives against SARS-CoV-2 solved structures. The bulky moieties (hydroxyl or fluorated phenyl moieties) added to the 2′ position of the ribose ring positively impacted the binding affinity to RdRp. The current in silico study represents a one-step-ahead for suggesting new possible blockers of SARS-CoV-2 RdRp that are yet to be verified in the wet lab. It offers new potential binders or blockers of RdRp that bind to the protein active site tighter than remdesivir. The latter was approved by the food and drug administration (FDA) for emergency use against COVID-19 last year.

According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting +250 M people.     

Assessing potential inhibitors of SARS-CoV-2 main protease from available drugs using free energy perturbation simulations

The main protease (Mpro) of the novel coronavirus SARS-CoV-2, which has caused the COVID-19 pandemic, is responsible for the maturation of its key proteins. Thus, inhibiting SARS-CoV-2 Mpro could prevent SARS-CoV-2 from multiplying. Because new inhibitors require thorough validation, repurposing current drugs could help reduce the validation process. Many recent studies used molecular docking to screen large databases for potential inhibitors of SARS-CoV-2 Mpro. However, molecular docking does not consider molecular dynamics and thus can be prone to error. In this work, we developed a protocol using free energy perturbation (FEP) to assess the potential inhibitors of SARS-CoV-2 Mpro. First, we validated both molecular docking and FEP on a set of 11 inhibitors of SARS-CoV-2 Mpro with experimentally determined inhibitory data. The experimentally deduced binding free energy exhibits significantly stronger correlation with that predicted by FEP (R = 0.94 ± 0.04) than with that predicted by molecular docking (R = 0.82 ± 0.08). This result clearly shows that FEP is the most accurate method available to predict the binding affinity of SARS-CoV-2 Mpro + ligand complexes. We subsequently used FEP to validate the top 33 compounds screened with molecular docking from the ZINC15 database. Thirteen of these compounds were predicted to bind strongly to SARS-CoV-2 Mpro, most of which are currently used as drugs for various diseases in humans. Notably, delamanid, an anti-tuberculosis drug, was predicted to inhibit SARS-CoV-2 Mpro in the nanomolar range. Because both COVID-19 and tuberculosis are lung diseases, delamanid has higher probability to be suitable for treating COVID-19 than other predicted compounds. Analysis of the complexes of SARS-CoV-2 Mpro and the top inhibitors revealed the key residues involved in the binding, including the catalytic dyad His14 and Cys145, which is consistent with the structural studies reported recently.

Free Energy Pertubation (FEP) can be used to accurately predict the binding affinity of a ligand to the main protease (Mpro) of the novel coronavirus SARS-CoV-2.     

Mutations in the genome of severe acute respiratory syndrome coronavirus 2: implications for COVID-19 severity and progression

Coronaviridae is a large family of enveloped, positive-strand RNA viruses that has plagued the world since it was discovered in humans in the 1960s. The recent severe acute respiratory syndrome coronavirus (SARS-CoV)-2 pandemic has already exceeded the number of combined cases and deaths witnessed during previous SARS-CoV and Middle East respiratory syndrome-CoV epidemics in the last two decades. This narrative review focuses on genomic mutations in SARS-CoV-2 and their impact on the severity and progression of COVID-19 in light of reported data in the literature. Notable SARS-CoV-2 mutations associated with open reading frames, the S glycoprotein, and nucleocapsid protein, currently circulating globally, are discussed along with emerging mutations such as those in the SARS-CoV-2 VUI 202012/01 variant in the UK and other European countries, the 484K.V2 and P.1 variants in Brazil, the B.1.617 variant in India, and South African variants 501Y.V2 and B.1.1.529 (omicron). These variants have the potential to influence the receptor binding domain, host–virus fusion, and SARS-CoV-2 replication. Correlating these mutations with disease dynamics could help us understand their pathogenicity and design appropriate therapeutics.     

Binding of inhibitors to the monomeric and dimeric SARS-CoV-2 Mpro

SARS-CoV-2 rapidly infects millions of people worldwide since December 2019. There is still no effective treatment for the virus, resulting in the death of more than one million patients. Inhibiting the activity of SARS-CoV-2 main protease (Mpro), 3C-like protease (3CLP), is able to block the viral replication and proliferation. In this context, our study has revealed that in silico screening for inhibitors of SARS-CoV-2 Mpro can be reliably done using the monomeric structure of the Mpro instead of the dimeric one. Docking and fast pulling of ligand (FPL) simulations for both monomeric and dimeric forms correlate well with the corresponding experimental binding affinity data of 24 compounds. The obtained results were also confirmed via binding pose and noncovalent contact analyses. Our study results show that it is possible to speed up computer-aided drug design for SARS-CoV-2 Mpro by focusing on the monomeric form instead of the larger dimeric one.

Binding of inhibitors to the monomeric SARS-CoV-2 Mpro is similar to the dimeric one.     

Anti-SARS-CoV-2 and cytotoxic activity of two marine alkaloids from green alga Caulerpa cylindracea Sonder in the Dardanelles

Caulerpa cylindracea Sonder is a green alga belonging to the Caulerpaceae family. This is the first chemical investigation of C. cylindracea in the Dardanelles which resulted in the isolation of four compounds, caulerpin (1), monomethyl caulerpinate (2), beta-sitosterol (3), and palmitic acid (4). Their structures were elucidated by spectroscopic analyses including 1D- and 2D NMR and mass. The isolated compounds 1 and 2 were tested against the SARS-CoV-2 viral targets spike protein and main protease (3CL) enzyme, and both compounds significantly inhibit the interaction of spike protein and ACE2, while the main protease activity was not significantly reduced. Docking studies suggested that compounds 1 and 2 may bind to the ACE2 binding pocket on spike, and compound 2 may also bind to an allosteric site on spike. As such, these compounds may inhibit the spike–ACE2 complex formation competitively and/or allosterically and have the potential to be used against SARS-CoV-2 virus infection. In addition, compounds 1 and 2 showed at least two-fold higher cytotoxicity against breast cancer cell lines MCF7 and MDA-MB-231 compared to the CCD fibroblast control cell line.

Isolated compounds 1 and 2 from Caulerpa cyclindracea inhibit the SARS-CoV-2 spike protein. Modelling studies suggest that the compounds may interfere with the spike-ACE2 interaction directly and also via an interaction with a spike allosteric site.     

Considering both small and large scale motions of vascular endothelial growth factor (VEGF) is crucial for reliably predicting its binding affinities to DNA aptamers

Vascular endothelial growth factor 165 (VEGF₁₆₅), a predominant isoform of VEGF signal proteins, is an ideal target for developing drugs against various diseases. It is composed of a heparin binding domain (HBD) and a receptor binding domain (RBD), which are connected by a flexible linker. Among the two domains, RBD is utilized in binding with the signal transduction protein, the VEGF receptor (VEGFR). None the less for its pharmaceutical importance, structure-based studies for developing drugs has been severely hindered by the lack of its whole structure determination, mainly owing to the existence of the flexible linker. Fortunately, the utilization of computer simulation methods can offer a possibility to circumvent this difficult issue. Here, we employ ensemble docking in combination with the anisotropic network model analysis to examine the interactions between DNA aptamers and VEGF₁₆₅. We model three-dimensional structures of aptamer variants based on their sequence information and perform docking calculations with the whole VEGF₁₆₅ structure. Indeed, we show that we can closely reproduce the experimental binding affinity order among different DNA aptamer variants by inclusively considering the flexible nature of VEGF. In addition, we address how DNA aptamer that binds to HBD of VEGF₁₆₅ impedes the interaction between VEGFR and VEGF₁₆₅ through RBD, even though HBD and RBD are rather distant. The present study illustrates that the flexible docking scheme employed here can be applied to tricky cases that involve flexible proteins with undetermined structures, toward effectively predicting ligand binding affinities to such proteins.

Considering both small and large scale motions of VEGF is crucial to predict its relative binding affinities to DNA aptamer variants with docking.     

ACE2 as a potential therapeutic target for pandemic COVID-19

SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host. This disturbs the dynamic equilibrium between the ACE/Ang II/AT1R axis and ACE2/Ang (1–7)/Mas receptor axis. Therefore, the clinically approved drugs belonging to (i) angiotensin converting enzyme (ACE) inhibitors such as captopril, and enalaprilat, (ii) angiotensin-receptor blockers (ARBs) such as losartan, candesartan, olmesartan, azilsartan, irbesartan, and telmisartan and (iii) the combination of ACE inhibitors and ARBs such as losartan with lisinopril and captopril with losartan, and (iv) recombinant ACE2, were studied for their ability to activate ACE2 in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. These clinically approved drugs were found to activate ACE2 that had been downregulated in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. Therefore, these drugs may be repurposed to re-activate the downregulated ACE2 of COVID-19 patients. These drugs either alone or in combination may be repurposed as prophylactics and therapeutics against SARS-CoV-2 virus.

SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host.     

Natural coumarins as potential anti-SARS-CoV-2 agents supported by docking analysis

COVID-19 is a global pandemic first identified in China, causing severe acute respiratory syndrome. One of the therapeutic strategies for combating viral infections is the search for viral spike proteins as attachment inhibitors among natural compounds using molecular docking. This review aims at shedding light on the antiviral potential of natural products belonging to the natural-products class of coumarins up to 2020. Moreover, all these compounds were filtered based on ADME analysis to determine their physicochemical properties, and the best 74 compounds were selected. Using virtual-screening methods, the selected compounds were investigated for potential inhibition of viral main protease (Mpro), viral methyltransferase (nsp16/10 complex), viral recognition binding domain (RBD) of S-protein, and human angiotensin-converting enzyme 2 (ACE2), which is the human receptor for viral S-protein targets, using molecular-docking studies. Promising potential results against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and methyltransferase (nsp16) are presented.

Potential of coumarins against Covid-19.