Structure-guided pharmacophore based virtual screening, docking, and molecular dynamics to discover repurposed drugs as novel inhibitors against endoribonuclease Nsp15 of SARS-CoV-2.

COVID-19 (Corona Virus Disease of 2019) caused by the novel 'Severe Acute Respiratory Syndrome Coronavirus-2' (SARS-CoV-2) has wreaked havoc on human health and the global economy. As a result, for new medication development, it's critical to investigate possible therapeutic targets against the novel virus. 'Non-structural protein 15' (Nsp15) endonuclease is one of the crucial targets which helps in the replication of virus and virulence in the host immune system. Here, in the current study, we developed the structure-based pharmacophore model based on Nsp15-UMP interactions and virtually screened several databases against the selected model. To validate the screening process, we docked the top hits obtained after secondary filtering (Lipinski's rule of five, ADMET & Topkat) followed by 100 ns molecular dynamics (MD) simulations. Next, to revalidate the MD simulation studies, we have calculated the binding free energy of each complex using the MM-PBSA procedure. The discovered repurposed drugs can aid the rational design of novel inhibitors for Nsp15 of the SARS-CoV-2 enzyme and may be considered for immediate drug development.

Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants.

The genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel epitopes were identified as immunogenic triggering immune responses and no toxic after investigation with in silico tools. Furthermore, we found these peptide vaccine candidates showed a significant binding affinity for MHC I and MHC II alleles in molecular docking investigations. We consider them to be promising targets for developing peptide-based vaccines against SARS-CoV-2. Subsequently, we designed two efficient multi-epitopes vaccines against the SARS-CoV-2, the first one based on potent MHC class I and class II T-cell epitopes of S (FPNITNLCPF-NYNYLYRLFR-MFVFLVLLPLVSSQC), M (MWLSYFIASF-GLMWLSYFIASFRLF), E (LTALRLCAY-LLFLAFVVFLLVTLA), and N (SPRWYFYYL-AQFAPSASAFFGMSR). The second candidate is the result of the tailoring of the first designed vaccine according to three classes of SARS-CoV-2 variants. Molecular docking showed that the protein-protein binding interactions between the vaccines construct and TLR2-TLR4 immune receptors are stable complexes. These findings confirmed that the final multi-epitope vaccine could be easily adapted to new viral variants. Our study offers a shortlist of promising epitopes that can accelerate the development of an effective and safe vaccine against the virus and its adaptation to new variants.Communicated by Ramaswamy H. Sarma.

Identification of core therapeutic targets for Monkeypox virus and repurposing potential of drugs against them: An in silico approach.

Monkeypox virus (mpox virus) outbreak has rapidly spread to 82 non-endemic countries. Although it primarily causes skin lesions, secondary complications and high mortality (1-10%) in vulnerable populations have made it an emerging threat. Since there is no specific vaccine/antiviral, it is desirable to repurpose existing drugs against mpox virus. With little knowledge about the lifecycle of mpox virus, identifying potential inhibitors is a challenge. Nevertheless, the available genomes of mpox virus in public databases represent a goldmine of untapped possibilities to identify druggable targets for the structure-based identification of inhibitors. Leveraging this resource, we combined genomics and subtractive proteomics to identify highly druggable core proteins of mpox virus. This was followed by virtual screening to identify inhibitors with affinities for multiple targets. 125 publicly available genomes of mpox virus were mined to identify 69 highly conserved proteins. These proteins were then curated manually. These curated proteins were funnelled through a subtractive proteomics pipeline to identify 4 highly druggable, non-host homologous targets namely; A20R, I7L, Top1B and VETFS. High-throughput virtual screening of 5893 highly curated approved/investigational drugs led to the identification of common as well as unique potential inhibitors with high binding affinities. The common inhibitors, i.e., batefenterol, burixafor and eluxadoline were further validated by molecular dynamics simulation to identify their best potential binding modes. The affinity of these inhibitors suggests their repurposing potential. This work can encourage further experimental validation for possible therapeutic management of mpox.

Molecular insights to the binding interactions of APNS containing HIV-protease inhibitors against SARS-CoV-2 Mpro: an in silico approach towards drug repurposing.

SARS-CoV-2 Mpro is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 Mpro. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 Mpro, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 Mpro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 Mpro by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (ΔGBind = -28.31 kcal/mol) due to an increased favorable van der Waals (ΔEvdw) interactions and decreased solvation (ΔGsolv) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (-6.85 kcal/mol), KNI-227 (-18.36 kcal/mol), KNI-272 (-15.69 kcal/mol) and KNI-1931 (-21.59 kcal/mol) against SARS-CoV-2 Mpro. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 Mpro drugs.Communicated by Ramaswamy H. Sarma.

In-silico INVESTIGATION OF FERULIC ACID DERIVATES AGAINST MAIN PROTEASE SARS-COV

Ferulic acid is one of the natural compounds which is prevalent in various plants. This compound has known to possess extensive biological activity to get good health and well-being. In this study, we designed 23 derivates of ferulic acid and evaluate their potency in silico as potential SARS-CoV Mpro inhibitors. Furthermore, in silico ADME profiles of designed compounds were evaluated to verify whether the ferulic acid analogs possess an acceptable pharmacokinetic profile. The molecular docking result using AutoDock 4.2.6 showed that compound FA-24, which contained dihydro benzoxazine moiety, possesses a better docking score among the designed compound. Five top compounds based on docking score (FA-16, FA-17, FA-18, FA-23, and FA-24) were then evaluated using molecular dynamics for 10 ns, followed by free binding energy evaluation using the MM-PBSA approach. The result indicated that all compounds formed stable complexes with the enzyme for 100 ns. However, MM-PBSA result showed that compound FA-16, which contained phenyl benzoate moiety, possess higher free binding energy. It is argued that this difference was due to the nature of free binding energy evaluation, which was based on molecular dynamics results. Although, both the docking score and free binding energy of the designed compound are lower than the native ligand (AZP), it is believed that further structure modification could be performed to address this shortcoming. Ultimately, all designed ferulic acid analogs possess optimal absorption and drug-likeness characteristic, while several compounds were predicted to interact with isoforms of CYP450. © 2022, Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma. All rights reserved.

Revisiting the South Indian Traditional Plants against Several Targets of SARS-CoV-2 - An in silico Approach.

BACKGROUND: The south Indian Telugu states will celebrate a new year called 'Ugadi' which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. OBJECTIVE: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. METHODS: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. RESULTS: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, - 82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. CONCLUSION: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.

Interfacial water molecules contribute to antibody binding to the receptor-binding domain of SARS-CoV-2 spike protein.

Antibodies that recognize the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially the neutralizing antibodies, carry great hope in the treatment and final elimination of COVID-19. Driven by a synchronized global effort, thousands of antibodies against the spike protein have been identified during the past two years, with the structural information available at atomistic detail for hundreds of these antibodies. We developed an improved molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method including explicitly treated interfacial water to calculate the binding free energy between representative antibodies and the receptor binding domain (RBD) domain of SARS-COV-2 spike proteins. We discovered that explicit treatment of water molecules located at the interface between RBD and antibody effectively improves the results for the WT and variants of concern (VOC) systems. Interfacial water molecules, together with surface and internal water molecules, behave drastically from bulk water and exert peculiar impacts on protein dynamics and energy, and thus warrant explicit treatment to complement implicit solvent models. Our results illustrate the importance of including interfacial water molecules to approach efficient and reliable prediction of binding free energy.Communicated by Ramaswamy H. Sarma.

Inhibition of multiple SARS-CoV-2 proteins by an antiviral biomolecule, seselin from Aegle marmelos deciphered using molecular docking analysis.

Our earlier experimental and computational report produced evidence on the antiviral nature of the compound seselin purified from the leaf extracts of Aegle marmelos against Bombyx mori Nuclear Polyhedrosis Virus (BmNPV). In the pandemic situation of COVID-19 caused by the SARS-COV-2 virus, an in silico effort to evaluate the potentiality of the seselin was made to test its efficacy against multiple targets of SARS-COV-2 such as spike protein S2, COVID-19 main protease and free enzyme of the SARS-CoV-2 (2019-nCoV) main protease. The ligand seselin showed the best interaction with receptors, spike protein S2, COVID-19 main protease and free enzyme of the SARS-CoV-2 (2019-nCoV) main protease with a binding energy of -6.3 kcal/mol, -6.9 kcal/mol and -6.7 kcal/mol, respectively. Docking analysis with three different receptors identified that all the computationally predicted lowest energy complexes were stabilized by intermolecular hydrogen bonds and stacking interactions. The amino acid residues involved in interactions were ASP1184, GLU1182, ARG1185 and SER943 for spike protein, SER1003, ALA958 and THR961 for COVID-19 main protease, and for SARS-CoV-2 (2019-nCoV) main protease, it was THR111, GLN110 and THR292. The MD simulation and MM/PBSA analysis showed that the compound seselin could effectively bind with the target receptors. The outcome of pharmacokinetic analysis suggested that the compound had favourable drugability properties. The results suggested that the seselin had inhibitory potential over multiple SARS-COV-2 targets and hold a high potential to work effectively as a novel drug for COVID-19 if evaluated in experimental setups in the foreseeable future. Communicated by Ramaswamy H. Sarma.

Identifying the natural compound Catechin from tropical mangrove plants as a potential lead candidate against 3CLpro from SARS-CoV-2: An integrated in silico approach.

SARS-CoV-2, a member of beta coronaviruses, is a single-stranded, positive-sense RNA virus responsible for the COVID-19 pandemic. With global fatalities of the pandemic exceeding 4.57 million, it becomes crucial to identify effective therapeutics against the virus. A protease, 3CLpro, is responsible for the proteolysis of viral polypeptides into functional proteins, which is essential for viral pathogenesis. This indispensable activity of 3CLpro makes it an attractive target for inhibition studies. The current study aimed to identify potential lead molecules against 3CLpro of SARS-CoV-2 using a manually curated in-house library of antiviral compounds from mangrove plants. This study employed the structure-based virtual screening technique to evaluate an in-house library of antiviral compounds against 3CLpro of SARS-CoV-2. The library was comprised of thirty-three experimentally proven antiviral molecules extracted from different species of tropical mangrove plants. The molecules in the library were virtually screened using AutoDock Vina, and subsequently, the top five promising 3CLpro-ligand complexes along with 3CLpro-N3 (control molecule) complex were subjected to MD simulations to comprehend their dynamic behaviour and structural stabilities. Finally, the MM/PBSA approach was used to calculate the binding free energies of 3CLpro complexes. Among all the studied compounds, Catechin achieved the most significant binding free energy (-40.3 ± 3.1 kcal/mol), and was closest to the control molecule (-42.8 ± 5.1 kcal/mol), and its complex with 3CLpro exhibited the highest structural stability. Through extensive computational investigations, we propose Catechin as a potential therapeutic agent against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Understanding the molecular interaction of SARS-CoV-2 spike mutants with ACE2 (angiotensin converting enzyme 2).

Covid-19 is a viral disease caused by the virus SARS-CoV-2 that spread worldwide and caused more than 4.3 million deaths. Moreover, SARS-CoV-2 still continues to evolve, and specifically the E484K, N501Y, and South Africa triple (K417N + E484K + N501Y) spike protein mutants remain as the 'escape' phenotypes. The aim of this study was to compare the interaction between the receptor binding domain (RBD) of the E484K, N501Y and South Africa triple spike variants and ACE2 with the interaction between wild-type spike RBD-ACE2 and to show whether the obtained binding affinities and conformations corraborate clinical findings. The structures of the RBDs of the E484K, N501Y and South Africa triple variants were generated with DS Studio v16 and energetically minimized using the CHARMM22 force field. Protein-protein dockings were performed in the HADDOCK server and the obtained wild-type and mutant spike-ACE2 complexes were submitted to 200-ns molecular dynamics simulations with subsequent free energy calculations using GROMACS. Based on docking binding affinities and free energy calculations the E484K, N501Y and triple mutant variants were found to interact stronger with the ACE2 than the wild-type spike. Interestingly, molecular dynamics and MM-PBSA results showed that E484K and spike triple mutant complexes were more stable than the N501Y one. Moreover, the E484K and South Africa triple mutants triggered greater conformational changes in the spike glycoprotein than N501Y. The E484K variant alone, or the combination of K417N + E484K + N501Y mutations induce significant conformational transitions in the spike glycoprotein, while increasing the spike-ACE2 binding affinity.Communicated by Ramaswamy H. Sarma.

Large scale peptide screening against main protease of SARS CoV-2.

The COVID-19 pandemic has been a public health emergency, with deadly forms constantly emerging around the world, highlighting the dire need for highly effective antiviral therapeutics. Peptide therapeutics show significant potential for this viral disease due to their efficiency, safety, and specificity. Here, two thousand seven hundred eight antibacterial peptides were screened computationally targeting the Main protease (Mpro) of SARS CoV-2. Six top-ranked peptides according to their binding scores, binding pose were investigated by molecular dynamics to explore the interaction and binding behavior of peptide-Mpro complexes. The structural and energetic characteristics of Mpro-DRAMP01760 and Mpro-DRAMP01808 complexes fluctuated less during a 250 ns MD simulation. In addition, three peptides (DRAMP01760, DRAMP01808, and DRAMP01342) bind strongly to Mpro protein, according to the free energy landscape and principal component analysis. Peptide helicity and secondary structure analysis are in agreement with our findings. Interaction analysis of protein-peptide complexes demonstrated that Mpro's residue CYS145, HIS41, PRO168, GLU166, GLN189, ASN142, MET49, and THR26 play significant contributions in peptide-protein attachment. Binding free energy analysis (MM-PBSA) demonstrated the energy profile of interacting residues of Mpro in peptide-Mpro complexes. To summarize, the peptides DRAMP01808 and DRAMP01760 may be highly Mpro specific, resulting disruption in a viral replication and transcription. The results of this research are expected to assist future research toward the development of antiviral peptide-based therapeutics for Covid-19 treatment.

Exploration of potential inhibitors for SARS-CoV-2 Mpro considering its mutants via structure-based drug design, molecular docking, MD simulations, MM/PBSA, and DFT calculations.

The main protease (Mpro) of SARS-COV-2 plays a vital role in the viral life cycle and pathogenicity. Due to its specific attributes, this 3-chymotrypsin like protease can be a reliable target for the drug design to combat COVID-19. Since the advent of COVID-19, Mpro has undergone many mutations. Here, the impact of 10 mutations based on their frequency and five more based on their proximity to the active site was investigated. For comparison purposes, the docking process was also performed against the Mpros of SARS-COV and MERS-COV. Four inhibitors with the highest docking score (11b, α-ketoamide 13b, Nelfinavir, and PF-07321332) were selected for the structure-based ligand design via fragment replacement, and around 2000 new compounds were thus obtained. After the screening of these new compounds, the pharmacokinetic properties of the best ones were predicted. In the last step, comparative molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA), and density functional theory calculations were performed. Among the 2000 newly designed compounds, three of them (NE1, NE2, and NE3), which were obtained by modifications of Nelfinavir, showed the highest affinity against all the Mpro targets. Together, NE1 compound is the best candidate for follow-up Mpro inhibition and drug development studies.

In-silico investigation of some recent natural compounds for their potential use against SARS-CoV-2: a DFT, molecular docking and molecular dynamics study.

Since its first appearance in December 2019, SARS-CoV-2 has infected many people all over the world, causing serious health problems in many people and causing many deaths, but no specific drug has been developed yet. SARS-CoV-2 main protease (SARS-CoV-2 Mpro) has an important role in viral replication and transcription, so inhibition of this enzyme is proposed to be an attractive route for the treatment of COVID-19. Natural compounds have been used in the treatment of many diseases throughout the history. In this study, it was aimed to investigate SARS-CoV-2 Mpro inhibition abilities, thus the therapeutic potentials of some novel phytochemicals which have recently been entered the literature. For this purpose, eleven novel phytochemicals obtained from various natural resources have been investigated for their potential antiviral activity against SARS-CoV-2 with the use of in silico methods. In the first part of the study, DFT (density functional theory) calculations were performed on the investigated compounds. In this part, geometry optimizations, vibrational analyses, and MEP (molecular electrostatic potential) map calculations were performed. In the second part, molecular docking calculations and then molecular dynamics (MD) simulations were performed to investigate how these natural compounds interact with SARS-CoV-2 Mpro which is a promising target for COVID-19 treatments. In this part, MM-PBSA (molecular mechanics with Poisson-Boltzmann surface area) calculations were also performed to determine the binding free energies of the investigated compounds. Results showed that most of the investigated compounds interacted with SARS-CoV-2 Mpro effectively and can be promising structures for drug development studies for COVID-19.Communicated by Ramaswamy H. Sarma.

In silico investigation of the interactions of certain drugs proposed for the treatment of Covid-19 with the paraoxonase-1.

Coronavirus disease 2019 (Covid-19) has caused one of the biggest pandemics of modern times, infected over 240 million people and killed over 4.9 million people, and continues to do so. Although many drugs are widely recommended in the treatment of this disease, the interactions of these drugs with an anti-atherosclerotic enzyme, paraoxonase-1 (PON1), are not well known. In our study, we investigated the interactions of 18 different drugs, which are claimed to be effective against covid-19, with the PON1 enzyme and its genetics variants L55M and Q192R with molecular docking, molecular dynamics simulation and free energy calculation method MM/PBSA. We found that ruxolitinib, dexamethasone, colchicine; dexamethasone, sitagliptin, baricitinib and galidesivir, ruxolitinib, hydroxychloroquine were the most effective compounds in binding PON1-w, PON1L55M and PON1Q192R respectively. Mainly, sitagliptin, galidesivir and hydroxychloroquine have attracted attention by showing very high affinity (<-300 kJ/mol) according to the MM/PBSA method. We concluded that the drug interactions should be considered and more attention should be paid in the use of these drugs.Communicated by Ramaswamy H. Sarma.

Design of hACE2-based small peptide inhibitors against spike protein of SARS-CoV-2: a computational approach.

COVID-19 which is caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has been declared pandemic in 2019. Though there is development of vaccines but there is an emergence requirement of drugs against SARS-CoV-2. Antiviral peptides can be rationally created and improved based on the known structures of viral proteins and their biological targets. In the given study, small peptide inhibitors with three amino acids are designed and docked against SARS-CoV-2 coronavirus using molecular docking approach. All the designed peptides bind at the active site but the highest binding affinity was observed for HisGluAsp. Molecular dynamics was performed to validate the stability and interactions of compound. The molecule has followed the druglikeness properties and with highest probability of being absorbed by the gastrointestinal tract. The results of the current investigation point to the possibility that the identified small peptides may prevent SARS-CoV-2 infection, although additional wet-lab tests are still required to confirm these results.

Multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis of the synergistic effects between natural compounds baicalein and cubebin for the inhibition of the main protease of SARS-CoV-2.

Combination drugs have been used for several diseases for many years since they produce better therapeutic effects. However, it is still a challenge to discover candidates to form a combination drug. This study aimed to investigate whether using a comprehensive in silico approach to identify novel combination drugs from a Chinese herbal formula is an appropriate and creative strategy. We, therefore, used Toujie Quwen Granules for the main protease (Mpro) of SARS-CoV-2 as an example. We first used molecular docking to identify molecular components of the formula which may inhibit Mpro. Baicalein (HQA004) is the most favorable inhibitory ligand. We also identified a ligand from the other component, cubebin (CHA008), which may act to support the proposed HQA004 inhibitor. Molecular dynamics simulations were then performed to further elucidate the possible mechanism of inhibition by HQA004 and synergistic bioactivity conferred by CHA008. HQA004 bound strongly at the active site and that CHA008 enhanced the contacts between HQA004 and Mpro. However, CHA008 also dynamically interacted at multiple sites, and continued to enhance the stability of HQA004 despite diffusion to a distant site. We proposed that HQA004 acted as a possible inhibitor, and CHA008 served to enhance its effects via allosteric effects at two sites. Additionally, our novel wavelet analysis showed that as a result of CHA008 binding, the dynamics and structure of Mpro were observed to have more subtle changes, demonstrating that the inter-residue contacts within Mpro were disrupted by the synergistic ligand. This work highlighted the molecular mechanism of synergistic effects between different herbs as a result of allosteric crosstalk between two ligands at a protein target, as well as revealed that using the multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis to discover novel combination drugs from a Chinese herbal remedy is an innovative pathway.

Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants.

To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBDWT-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBDOMIs) feature increased global structural fluctuations when compared with RBDWT. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBDOMIs than RBDWT, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBDBA.4/5) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBDBA.4/5 results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences.

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19.

The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus's spike protein. The cleavage site facilitates the entry of the virus into human cells via cell-cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of - 7 kcal.mol-1, pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between - 189 and - 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02056-1.

Free energy perturbation-based large-scale virtual screening for effective drug discovery against COVID-19

As a theoretically rigorous and accurate method, FEP-ABFE (Free Energy Perturbation-Absolute Binding Free Energy) calculations showed great potential in drug discovery, but its practical application was difficult due to high computational cost. To rapidly discover antiviral drugs targeting SARS-CoV-2 M- pro and TMPRSS2, we performed FEP-ABFE-based virtual screening for similar to 12,000 protein-ligand binding systems on a new generation of Tianhe supercomputer. A task management tool was specifically developed for automating the whole process involving more than 500,000 MD tasks. In further experimental validation, 50 out of 98 tested compounds showed significant inhibitory activity towards M- pro , and one representative inhibitor, dipyridamole, showed remarkable outcomes in subsequent clinical trials. This work not only demonstrates the potential of FEP-ABFE in drug discovery but also provides an excellent starting point for further development of anti-SARS-CoV-2 drugs. Besides, similar to 500 TB of data generated in this work will also accelerate the further development of FEP-related methods.