GC-MS analysis of phytoconstituents from Ruellia prostrata and Senna tora and identification of potential anti-viral activity against SARS-CoV-2

SARS-CoV-2 is an etiologic agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. The virus has rapidly extended globally and taken millions of lives due to the unavailability of therapeutics candidates against the virus. Till now, no specific drug candidates have been developed that can prevent or treat infections caused by the pathogen. The main protease (M^pro) of the SARS-CoV-2 plays a pivotal role in mediating viral replication and mechanistically inhibition of the protein can hinder the replication and infection process of the virus. Therefore, the study aimed to identify the natural bioactive compounds against the virus that can block the activity of the M^pro and subsequently block viral infections. Initially, a total of 96 phytochemicals from Ruellia prostrata Poir. and Senna tora (L.) Roxb. plants were identified through the gas chromatography-mass spectrometry (GC-MS) analytical method. Subsequently, the compounds were screened through molecular docking, absorption, distribution, metabolism, excretion (ADME), toxicity (T), and molecular dynamics (MD) simulation approach. The molecular docking method initially identified four molecules having a PubChem CID: 70825, CID: 25247358, CID: 54685836 and, CID: 1983 with a binding affinity ranging between −6.067 to −6.53 kcal mol⁻¹ to the active site of the target protein. All the selected compounds exhibit good pharmacokinetics and toxicity properties. Finally, the four compounds were further evaluated based on the MD simulation methods that confirmed the binding stability of the compounds to the targeted protein. The computational approaches identified the best four compounds CID: 70825, CID: 25247358, CID: 54685836 and, CID: 1983 that can be developed as a treatment option of SARS-CoV-2 disease-related complications. Although, experimental validation is suggested for further evaluation of the work.

Protease (M^pro) of SARS-CoV-2 has been identified as being able to hinder the replication process of the virus. Using GC-MS analytical methods, phytochemicals were identified from different medicinal plants that resulted in inhibitory activity of the molecules against M^pro.     

Drug repurposing and computational modeling for discovery of inhibitors of the main protease (Mpro) of SARS-CoV-2

The main protease (M^pro or 3CL^pro) is a conserved cysteine protease from the coronaviruses and started to be considered an important drug target for developing antivirals, as it produced a deadly outbreak of COVID-19. Herein, we used a combination of drug reposition and computational modeling approaches including molecular docking, molecular dynamics (MD) simulations, and the calculated binding free energy to evaluate a set of drugs in complex with the M^pro enzyme. Particularly, our results show that darunavir and triptorelin drugs have favorable binding free energy (−63.70 and −77.28 kcal mol⁻¹, respectively) in complex with the M^pro enzyme. Based on the results, the structural and energetic features that explain why some drugs can be repositioned to inhibit M^pro from SARS-CoV-2 were exposed. These features should be considered for the design of novel M^pro inhibitors.

Structural and energetic features explain why some drugs can be repositioned to inhibit M^pro from SARS-CoV-2.     

The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies

An investigation has been carried out on natural products from dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CL^pro) using an in silico approach. Inhibition of the 3CL^pro enzyme is a promising target in stopping the replication of the SARS-CoV-2 virus through inhibition of the subsite binding pocket. The redocking process aims to determine the 3CL^pro active sites. The redocking requirement showed a good pose with an RMSD value of 1.39 Å. The combination of molecular docking and MD simulation shows the results of DD13 as a candidate which had a good binding affinity (kcal mol⁻¹) to inhibit the 3CL^pro enzyme activity. Prediction of binding free energy (kcal mol⁻¹) of DD13 using the Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB/GBSA) approach shows the results ΔG_{bind(MM-GBSA)}: −52.33 ± 0.34 and ΔG_{bind(MM-PBSA)}: −43.52 ± 0.42. The key residues responsible for the inhibition mechanism are Hie41, Ser46, Met49, Asn142, Cys145, Hie163, Met165, and Gln189. Additionally, pharmacokinetic prediction recommended that DD13 had promising criteria as a drug candidate. The results demonstrated in this study provide theoretical information to obtain a potential inhibitor against the SARS-CoV-2 main protease.

An investigation on dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CL^pro) using an in silico approach.     

In silico study of natural compounds from sesame against COVID-19 by targeting Mpro,PLpro and RdRp

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (M^pro), papain-like protease (PL^pro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 M^pro that exceeded the currently used SARS-CoV-2 M^pro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PL^Pro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from −4.9 to −8.8 kcal mol⁻¹. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski''s rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads.     

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.     

Two novel oxetane containing lignans and a new megastigmane from Paronychia arabica and in silico analysis of them as prospective SARS-CoV-2 inhibitors

The chemical characterization of the extract of the aerial parts of Paronychia arabica afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known lignan (4), eight known phenolic compounds (5–12), one known elemene sesquiterpene (13) and one steroid glycoside (14). The chemical structures of the isolated compounds were constructed based upon the HRMS, 1D, and 2D-NMR results. The absolute configurations were established via NOESY experiments as well as experimental and TDDFT-calculated electronic circular dichroism (ECD). Utilizing molecular docking, the binding scores and modes of compounds 1–3 towards the SARS-CoV-2 main protease (M^pro), papain-like protease (PL^pro), and RNA-dependent RNA polymerase (RdRp) were revealed. Compound 3 exhibited a promising docking score (−9.8 kcal mol⁻¹) against SARS-CoV-2 M^pro by forming seven hydrogen bonds inside the active site with the key amino acids. The reactome pathway enrichment analysis revealed a correlation between the inhibition of GSK3 and GSK3B genes (identified as the main targets of megastigmane treatment) and significant inhibition of SARS-CoV-1 viral replication in infected Vero E6 cells. Our results manifest a novel understanding of genes, proteins and corresponding pathways against SARS-CoV-2 infection and could facilitate the identification and characterization of novel therapeutic targets as treatments of SARS-CoV-2 infection.

The hydromethanolic extract of Paronychia arabica aerial parts afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known secondary metabolites (4–14).     

Versisterol,a new endophytic steroid with 3CL protease inhibitory activity from Avicennia marina (Forssk.) Vierh.

A new epoxy ergostane sterol, named versisterol, was isolated from Aspergillus versicolor, an endophytic fungus from Avicennia marina. The structure of the isolated compound was deduced by means of one- and two-dimensional NMR and high-resolution mass spectrometry. The absolute stereochemistry was elucidated by NOESY analysis, and experimental and calculated time-dependent density functional theory (TD-DFT) circular dichroism spectroscopy. Versisterol inhibited 3CL protease (3CL^pro) with an IC₅₀ value of 2.168 ± 0.09 μM. Binding affinities and molecular interactions of versisterol towards 3CL^pro were scrutinized and compared to lopinavir with the help of the combination of docking computations and molecular dynamics (MD) simulation. In silico calculations demonstrated a comparable binding affinity of versisterol with a docking score of −9.4 kcal mol⁻¹, and MM-GBSA binding energy over 200 ns MD simulation of −29.1 kcal mol⁻¹, with respect to lopinavir (−9.8 and −32.2 kcal mol⁻¹, respectively). These findings suggested that versisterol can be an auspicious prototype for developing new 3CL^pro drug candidates against COVID-19.

A new epoxy ergostane sterol, named versisterol, was isolated from Aspergillus versicolor, an endophytic fungus from Avicennia marina.     

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).     

Theoretical insights into the effect of halogenated substituent on the electronic structure and spectroscopic properties of the favipiravir tautomeric forms and its implications for the treatment of COVID-19

In this study, we systematically investigated the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective. Additionally, the effects of hydration on the proton transfer mechanism of the tautomeric forms of the halogenated favipiravir compounds are discussed. Our results suggest that spectroscopic properties allow for the elucidation of such tautomeric forms. As is well-known, the favipiravir compound has excellent antiviral properties and hence was recently tested for the treatment of new coronavirus (SARS-CoV-2). Through in silico modeling, in the current study, we evaluate the role of such tautomeric forms in order to consider the effect of drug-metabolism in the inhibition process of the main protease (M^pro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus. According to the molecular docking, all halogenated compounds presented a better interaction energy than the co-crystallized active ligand (−3.5 kcal mol⁻¹) in the viral RdRp, in both wild-type (−6.3 to −6.5 kcal mol⁻¹) and variant (−5.4 to −5.6 kcal mol⁻¹) models. The variant analyzed for RdRp (Y176C) decreases the affinity of the keto form of the compounds in the active site, and prevented the ligands from interacting with RNA. These findings clearly indicated that all these compounds are promising as drug candidates for this molecular target.

In this study, we systematically investigated the electronic structure, spectroscopic properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective.     

In vitro and in silico studies of SARS-CoV-2 main protease Mpro inhibitors isolated from Helichrysum bracteatum

Discovering SARS-CoV-2 inhibitors from natural sources is still a target that has captured the interest of many researchers. In this study, the compounds (1–18) present in the methanolic extract of Helichrysum bracteatum were isolated, identified, and their in vitro inhibitory activities against SARS-CoV-2 main protease (M^pro) was evaluated using fluorescence resonance energy transfer assay (FRET-based assay). Based on 1D and 2D spectroscopic techniques, compounds (1–18) were identified as 24-β-ethyl-cholesta-5(6),22(23),25(26)-triene-3-ol (1), α-amyrin (2), linoleic acid (3), 24-β-ethyl-cholesta-5(6),22(23),25(26)-triene-3-O-β-d-glucoside (4), 1,3-propanediol-2-amino-1-(3′,4′-methylenedioxyphenyl) (5), (−)-(7R,8R,8′R)-acuminatolide (6), (+)-piperitol (7), 5,7,4′-trihydroxy-8,3′-dimethoxy flavanone (8), 5,7,4′-trihydroxy-6-methoxy flavanone (9), 4′,5-dihydroxy-3′,7,8-trimethoxyflavone (10), 5,7-dihydroxy-3′,4′,5′,8-tetramethoxy flavone (11), 1,3-propanediol-2-amino-1-(4′-hydroxy-3′-methoxyphenyl) (12), 3′,5′,5,7-tetrahydroxy-6-methoxyflavanone (13), simplexoside (piperitol-O-β-d-glucoside) (14), pinoresinol monomethyl ether-β-d-glucoside (15), orientin (16), luteolin-3′-O-β-d-glucoside (17), and 3,5-dicaffeoylquinic acid (18). Compounds 6, 12, and 14 showed comparable inhibitory activities against SARS-CoV-2 M^pro with IC₅₀ values of 0.917 ± 0.05, 0.476 ± 0.02, and 0.610 ± 0.03 μM, respectively, compared with the control lopinavir with an IC₅₀ value of 0.225 ± 0.01 μM. The other tested compounds showed considerable inhibitory activities. The molecular docking study for the tested compounds was carried out to correlate their binding modes and affinities for the SARS-CoV-2 M^pro enzyme with the in vitro results. Analyzing the results of the in vitro assay together with the obtained in silico results led to the conclusion that phenylpropanoids, lignans, and flavonoids could be considered suitable drug leads for developing anti-COVID-19 therapeutics. Moreover, the phenylpropanoid skeleton oxygenated at C3, C4 of the phenyl moiety and at C1, C3 of the propane parts constitute an essential core of the SARS-CoV-2 M^pro inhibitors, and thus could be proposed as a scaffold for the design of new anti-COVID-19 drugs.

Compounds isolated and identified from Helichrysum bracteatum leaves showed promising in vitro inhibitory activities against SARS-CoV-2 main protease (M^pro). Thus, could be considered suitable drug leads for developing anti-COVID-19 therapeutics.     

An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (M^pro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with M^pro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4, together with three known compounds, ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, was isolated from peach fruits.     

Chemical constituents from Limonium tubiflorum and their in silico evaluation as potential antiviral agents against SARS-CoV-2

Wild plants growing in the Egyptian deserts are facing abiotic stress, which can lead to interesting & safe natural products possessing potential chemical profiles. Consequently, our study was designed to assess the phytochemical composition of the aerial parts of Limonium tubiflorum (family Plumbaginaceae) growing wild in Egypt for the first time. In addition, in silico screening and molecular dynamic simulation of all isolated phytoconstituents were run against the main protease (M^pro) and spike glycoprotein SARS-CoV-2 targets which displayed a crucial role in the replication of this virus. Our findings showed that the phytochemical investigation of 70% ethanol extract of L. tubiflorum aerial parts afforded six known flavonoids; myricetin 3-O-(2′′-galloyl)-β-d-galactopyranoside (1), myricetin 3-O-(2′′-galloyl)-α-l-rhamnopyranoside (2), myricetin 3-O-(3′′-galloyl)-α-l-rhamnopyranoside (3), myricetin 3-O-β-d-galactopyranoside (5), apigenin (6), myricetin (7), along with two known phenolic acid derivatives; gallic acid (4) and ethyl gallate (8). Docking studies revealed that compounds (1) & (2) were the most effective compounds with binding energies of −17.9664 & −18.6652 kcal mol⁻¹ against main protease and −18.9244 & −18.9272 kcal mol⁻¹ towards spike glycoprotein receptors, respectively. The molecular dynamics simulation experiment agreed with the docking study and reported stability of compounds (1) and (2) against the selected targets which was proved by low RMSD for the tested components. Moreover, the structure–activity relationship revealed that the presence of the galloyl moiety is necessary for enhancement of the activity. Overall, the galloyl substructure of myricetin 3-O-glycoside derivatives (1 and 2) isolated from L. tubiflorum may be a possible lead for developing COVID-19 drugs. Further, in vitro and in vivo assays are recommended to support our in silico studies.

Wild plants growing in the Egyptian deserts are facing abiotic stress, which can lead to interesting & safe natural products possessing potential chemical profiles.     

Several coumarin derivatives and their Pd(ii) complexes as potential inhibitors of the main protease of SARS-CoV-2, an in silico approach

The global pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused many fatalities among people and significantly influenced the global economy. Since efficient treatment is not available, the computational methods in biology and chemistry are a promising starting point towards adequate medication. Three previously synthesized coumarin derivatives and their Pd(ii) complexes were examined for the binding affinity towards the M^pro protein of SARS-CoV-2 by molecular docking and compared to two Food and Drug Administration (FDA) drugs, cinanserin and chloroquine. All of the investigated compounds bind to the active position of the mentioned protein. Coumarin–Pd(ii) complexes showed higher binding affinities compared to the approved drugs. The bindings of the bis(3-(1-((3-chlorophenyl)amino)ethylidene)-chroman-2,4-dione) palladium(ii) complex, its corresponding ligand, and cinanserin to SARS-CoV-2 M^pro were further subjected to the molecular dynamics simulations. The binding free energies, computed by MM/PBSA approach were analyzed in detail and the importance of specific interactions outlined. These results showed that the molecules bearing structural similarity to the approved drugs and their complexes have the potential to inhibit the functional activity of SARS-CoV-2 protease and further experimental studies should be undertaken.

Coumarin derivatives and their Pd(ii)-complexes have shown a higher binding potential towards SARS-CoV-2 M^pro than chloroquine/cinanserin along with lower toxicity.     

Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 Mpro

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

The catalytic triad Cys145–His41–Asp187 of SARS-CoV-2 M^pro plays an important role in the activation of the PF-07321332 covalent inhibitor.     

Synthesis,crystal structure and in silico studies of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

Herein, acetic acid mediated multicomponent synthesis of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-one (2,4-dimethoxy-THPQs) was reported. Single-crystal XRD analysis of four newly developed crystals of 2,4-dimethoxy-THPQs and their DFT study were also reported. The structure of all molecules was optimized using DFT B3LYP/6-31G(d) level and compared with the corresponding single-crystal XRD data. As a result, the theoretical and experimental geometrical parameters (bond lengths and bond angles) were found to be in good agreement. Frontier molecular orbital (FMO) and molecule electrostatic potential (MEP) analyses were used to investigate the physicochemical properties and relative reactivity of 2,4-dimethoxy-THPQs. The formation of strong C–H⋯O and N–H⋯O interaction was investigated by Hirshfeld analysis. Furthermore, electronic charge density concentration in 2,4-dimethoxy-THPQs was analysed by the Mulliken atomic charges which helps to predict the ability of 2,4-dimethoxy-THPQs to bind in the receptor. The molecular docking of the crystal structure of 2,4-dimethoxy-THPQs in the main protease (M^pro) of SARS-CoV-2 suggested that all four 2,4-dimethoxy-THPQs efficiently docked in M^pro. Furthermore, 2,4-dimethoxy-THPQs with a 3-chloro substitution in the phenyl ring have the highest binding affinity because of the additional formation of halogen bonds and highest dipole moment.

Single-crystal XRD analysis of 2,4-dimethoxy THPQs and their relative reactivity with properties were investigated using DFT calculation. Molecular docking studies show they effectively docked with main protease of SARS-CoV-2.     

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.     

The interactions of folate with the enzyme furin: a computational study

Entrance of coronavirus into cells happens through the spike proteins on the virus surface, for which the spike protein should be cleaved into S1 and S2 domains. This cleavage is mediated by furin, a member of the proprotein convertases family, which can specifically cleave Arg-X-X-Arg↓ sites of the substrates. Here, folate (folic acid), a water-soluble B vitamin, is introduced for the inhibition of furin activity. Therefore, molecular insight into the prevention of furin activity in the presence of folic acid derivatives is presented. To this aim, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations were performed to clarify the inhibitory mechanism of these compounds. In this regard, molecular docking studies were conducted to probe the furin binding sites of folic acid derivatives. The MD simulation results indicated that these drugs can efficiently bind to the furin active site. While the folic acid molecule tended to be positioned slightly towards the Glu271, Tyr313, Ala532, Gln488, and Asp530 amino acids of furin at short and long ranges, the folinic acid molecule interacted with Glu271, Ser311, Arg490, Gln488, and Lys499 amino acids. Consequently, binding free energy calculations illustrated that folic acid (−27.90 kcal mol⁻¹) has better binding in comparison with folinic acid (−12.84 kcal mol⁻¹).

The present study introduces the ability of folic acid to interact and inhibit furin proprotein.     

Design,synthesis and in silico screening of benzoxazole–thiazolidinone hybrids as potential inhibitors of SARS-CoV-2 proteases

Hybrid molecules in the recent years have gained significant importance in drug research as promising therapeutic agents. We report a novel combination of two such bioactive scaffolds (benzoxazole and 4-thiazolidinone B–T hybrids) as inhibitors of SARS-CoV-2. The study uses an in silico approach to identify the potential of B–T hybrids as possible inhibitors of the SARS-CoV-2 proteases. Molecular docking was employed to identify the interactions of B–T hybrids with the two proteases – 3CLp (the 3-chymotrypsin-like protease) and PLp (the papain-like protease). Docking results of the screened 81 hybrids indicated that BT10 and BT14 interacted with the catalytic dyad residue of 3CLp (Cys145) with the best binding energy. MD simulations revealed that BT10 formed stable interactions via 4 hydrogen bonds with the catalytic site residues of 3CLp. In the case of PLp, BT27 and MBT9 interacted with the catalytic triad residue of PLp (His272) with high binding energy. MD simulations demonstrated that the reference drug Tipranavir relocated to the thumb region of the protease whereas BT27 remained in the active site of PLp stabilized by 2 hydrogen bonds, while MBT9 relocated to the BL2 loop of the palm region. The MM-PBSA and interaction entropy (IE) analysis indicated that BT14 exhibited the best ΔG (of −6.83 kcal mol⁻¹) with 3CLp, while BT27 exhibited the best ΔG (of −7.76 kcal mol⁻¹) with PLp. A four-step synthetic procedure was employed to synthesize the B–T hybrids starting from ammonium thiocyanate. The short-listed compounds in the case of 3CLp were synthesized and characterized using IR, NMR, and HRMS spectroscopic techniques.

A novel combination of two bioactive scaffolds – benzoxazole and 4-thiazolidinone (B–T hybrids) as potential inhibitors of SARS-CoV-2.