INITIAL STUDY ON SARS-COV-2 MAIN PROTEASE INHIBITION MECHANISM OF SOME POTENTIAL DRUGS USING MOLECULAR DOCKING SIMULATION

The infection by the new coronavirus SARS-CoV-2 (called as COVID-19 disease) is a worldwide emergency, however, there is no antiviral treatment or vaccine to date. 3C like protease (3CLpro) is the main protease of SARS-CoV-2 that involved in the process of translation of the polypeptide from the genomic RNA to protein components, which are required for virus replication. The crystal structure of this protease has been rapidly resolved and made publicly in the Protein Data Bank recently. Many efforts have been conducted by scientists including the use of several commercial medicines that are known for treatment of HIV and anti-malarial/antibiotic such as arbidol, chloroquine, hydroxychloroquine, azithromycin, darunavir, remdesivir and lopinavir/ritonavir. These drugs exhibited significant efficacy in clinical, however, the understanding at atomic level of how these compounds prevent SARS-CoV-2 protease is still lacking. Therefore, in this context docking protocol was employed to rapidly estimate the binding affinity and binding pose of six drugs on the main protease of SARS-CoV-2 virus. The obtained results might help to shed light on the interaction mechanism of these compounds toward the protein, and thus suggesting an efficient approach to drug discovery and treatments. © 2020, Publishing House of Natural Science and Technology, VAST. All rights reserved.

Molecular Docking Strategy for Multi-Target Inhibitor Discovery of Selected Plant Constituents in Bauhinia Acuminata

Objective: Traditional medicine is often considered to be a kind of complementary or alternative medicine (CAM) nowadays. Therefore, documenting and identifying the herbs that are effective in treating various diseases is vital for future disease control programs. This study aims to perform a molecular docking analysis of the thirteen plant components in Bauhinia acuminata against the target proteins in lung cancer (PDB IDs: 2ITY), breast cancer (1A52), diabetes (3L4U), obesity (IT02), inflammation (5COX) and corona viral infections (6VYO). Material(s) and Method(s): All the plant components used for the present study were retrieved from the plant Bauhinia acuminata and were evaluated for their biological activity results using molinspiration. Further in-silico docking analysis was performed using AutoDock Vina software and the binding interactions were visualized using Discovery studio program. Result and Discussion: The docking scores and analysis of the interactions of the plant components with targets suggest that all the selected plant components showed excellent binding to the chosen targets when compared to that of the standard drugs. As a result of the docking process on 6 different targets, the selected plant components like Quercetin, Beta-sitosterol, and Rheagenine were observed to show good binding energy values against all the 5 targets except 6VYO as shown in (Table 9). These results can further pave the way for getting better insights in identifying and designing potential lead candidates.Copyright © 2022 University of Ankara. All rights reserved.

Computational Interaction Study of Immunomodulatory Plant Derivatives Against SARS-Cov-2 Mpro Target

The COVID-19 pandemic has been reported to have a high incidence of morbidity and mortality, resulting in a large number of human deaths over the world. Studies suggest the importance of natural phytocompounds as potential antiviral agents and hypothesize to use them as therapeutics against COVID-19 main protease target. This study aims to identify a therapeutically potential natural compound from the immunomodulatory plants to inhibit the progression of the SARS CoV-2 virus. A total 8 major constituents, from various immunomodulatory-medicinal plants used in ayurvedic kadha preparation i.e. Cinnamon species (Dalchini), Piper nigrum (Kaali Mirch), Ocimum tenuiflorum (Tulsi), Zingiber officinale (Ginger), and Withania somnifera (Ashwagandha), have been used to perform docking with drug target main protease structure (SARS-CoV-2 Mpro, PDB ID: 6LU7) followed by molecular simulations. The pharmacological evaluations such as drug likeliness and ADMET properties calculations and RMSD calculation for 50 ns time scale of molecular dynamics support the current investigation. This study provides evidence of comparative significance with possible computational validations for Withaferin A of W. somnifera (Ashwagandha) with therapeutic potential towards SARS-CoV-2 Mpro, as a lead molecule. This chapter shows the different properties of natural phytocompounds, which are available in ayurvedic kadha as described by the government of India. Further, it details about different computational softwares/pipelines (off lines/online, Free/commercial) used for molecular docking and dynamics analysis. The chapter explains all the associated steps/execution of programs with a demonstration of the antiviral capacity of the phytocompounds from immunomodulatory plants through the case study. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.

Green synthesis, Single-Crystal X-RD, Hirshfeld Analysis and Anti-Covid-19 Molecular Docking Investigation of Symmetrical Azines

The 1,2-bis(3,4-dimethoxybenzylidene)hydrazine (VAHD) and 1,2-bis(3-methoxy-4-hydroxybenzylidene)hydrazine (VNHD) are synthesised in a solvent free and catalyst free by greener method (MW). Both the compounds are characterized by FT-IR,1H NMR and 13C NMR spectral studies. Single crystal XRD analysis provides more information on the structure of the compounds VAHD and VNHD. The energy gap (Eg), frontier orbital energies (EHOMO, ELUMO) and reactivity parameters like chemical hardness and global hardness andMulliken charges are calculated using density functional theory with B3LYP/6-311++G(d,p) basis set. The experimental and theoretical calculated IR frequencies and NMR chemical shifts values are compared by DFT method. Hirshfeld surface analysis was conducted to study structure and molecular properties. Molecular docking of symmetrical azine at the active sites of SARS-COVID receptors was investigated. Furthermore, the swissADME online application was used to analyse the physicochemical and pharmacokinetic features of the compounds (VAHD and VNHD). © 2023 Wiley-VCH GmbH.

In Silico Screening of Some Anti-Cancer Drugs Against the Main Protease of COVID-19 Using Molecular Docking

The SARS-CoV-2 pandemic has led to major worldwide health concerns. Design and detection of effective drugs and adjuvant therapies to treat COVID-19 disease in the shortest possible time have become one of the most critical global challenges. In this study, we investigated the effect of some anticancer drugs against the COVID-19 main protease (Mpro/3CLpro) to detect an effective treat-ment, using a molecular docking approach as a fast and cost-effective method. Accordingly, 44 anti-cancer drugs were selected as a target for the virtual screening. The molecular docking study was car-ried out using AutoDock Tools (ADT), AutoDock Vina, Discovery Studio, and Open Babel software. Tucatinib, selinexor, irinotecan, olaparib, dacomitinib, lapatinib, ibrutinib, and pazopanib were ranked top as COVID-19 inhibitors with the respective binding energy of-10.1,-9.4,-9.2,-8.9,-8.7,-8.7,-8.6, and-8.5 kcal/mol. Among the drugs tested, tucatinib displayed the highest binding affinity and strong interactions with the active site of COVID-19 3CLpro (-10.1 kcal/mol). Pharmacokinetics properties and drug-likeness of the top 8 selected anticancer drugs were evaluated. The results showed that these drugs could be utilized as potential inhibitors against the main protease of COVID-19, which can help control the spread of this disease. However, in vitro, in vivo studies, and clinical trials will help evalu-ate the efficacy of these drugs against COVID-19. © 2023 Bentham Science Publishers.

In Silico Identification of 1-DTP Inhibitors of Corynebacterium diphtheriae Using Phytochemicals from Andrographis paniculata.

A number of phytochemicals have been identified as promising drug molecules against a variety of diseases using an in-silico approach. The current research uses this approach to identify the phyto-derived drugs from Andrographis paniculata (Burm. f.) Wall. ex Nees (AP) for the treatment of diphtheria. In the present study, 18 bioactive molecules from Andrographis paniculata (obtained from the PubChem database) were docked against the diphtheria toxin using the AutoDock vina tool. Visualization of the top four molecules with the best dockscore, namely bisandrographolide (-10.4), andrographiside (-9.5), isoandrographolide (-9.4), and neoandrographolide (-9.1), helps gain a better understanding of the molecular interactions. Further screening using molecular dynamics simulation studies led to the identification of bisandrographolide and andrographiside as hit compounds. Investigation of pharmacokinetic properties, mainly ADMET, along with Lipinski's rule and binding affinity considerations, narrowed down the search for a potent drug to bisandrographolide, which was the only molecule to be negative for AMES toxicity. Thus, further modification of this compound followed by in vitro and in vivo studies can be used to examine itseffectiveness against diphtheria.

REVIEW: AUTODOCK 426 AS AN EFFECTIVE TOOL FOR MOLECULAR DOCKING STUDIES AGAINST SARS-COV-2 MAIN PROTEASE: A TUTORIAL USING MGLTOOLS

The worldwide pandemic caused by coronavirus SARS-CoV-2 (so called as COVID-19 disease) has affected 219 countries and territories, leading to numerous deaths and global financial crisis. The main protease (Mpro) of SARS-CoV-2 plays an important role in mediating the transcription and replication of virus, thus, one of the main therapeutic measures is to find compounds capable of inhibiting these enzymes as soon as possible. Nowadays, computer-aided drug design plays an important role in the field of drug discovery. In particular, molecular docking is one of the initial steps that effectively screen a numerous number of compounds for their interaction and binding affinity toward targeted enzyme, therefrom, suggesting a short list of potential inhibitors for further drug development processes. As part of our ongoing program to provide simple guideline for scientific community to utilize different docking tools for research purposes, in this article, a complete manual guideline of Autodock 4.2.6 is presented to demonstrate the simulation of interaction between compound PF-07321332 and the main protease of SARS-CoV-2, thereby suggesting an effective tool for scientists to conduct reseach on this disease. © 2022, Publishing House of Natural Science and Technology, VAST. All rights reserved.

In-silico Screening of Some Important Bioactive Compounds as Potential Inhibitors of 3CLpro Protein of SARS-CoV-2 and MERS-CoV Virus

Background: Coronavirus (SARS-CoV-2), the leading cause of the epidemic in 2019, also known as COVID-19, has raised ongoing global concerns. The most favourable target protein for this flu is 3CLpro (conserved 3-chymotrypsin-like protease), also known as Mpro. Covaxin and Covishield vaccination is going in India. Remdesivir, as well as some antimalarial drugs such as Hydroxychloroquine and Chloroquine, are used for extreme necessity. However, Hydroxychloroquine and Chloroquine and their derivatives are not convenient for those who are suffering from hypertension, diabetes, cardiac arrest, and many more. Objective: Here, we choose some bioactive compounds for docking studies with the Mpro of SARS CoV2 and MERS as it is used as the primary target for a comparative study. Methods: The docking process was carried out by preparing both 3CLpro proteins, i.e., 2YNA and 6LU7, and then the ligand molecules were downloaded from Pubchem, DrugBank, and Zinc15 databases. Furthermore, SwissAdme and pkCSM software were used for the determination of toxicity and Pharmacokinetic properties (ADMET) properties. Lastly, docking was carried out by the Autodock version 4.2 program, and the docking score was compared to the reference inhibitor Ritonavir. Results: Among 17 bioactive compounds used for docking studies, Quercetin, Trans-Resveratol, Kaemferol, and Theaflavin have top, binding affinity for target proteins, i.e., Theaflavin (-14.35 kcal/mol), Quercetin (-11.88kcal/mol), Kaempferol (-9.3 kcal/mol) and Trans-Resveratol (-9.31 kcal/mol) and also obey Lipinski's rule which makes them potential drug candidate against Covid-19 virus. Hence, the application of these plant-based bioactive compounds alone or along with scheduled vaccination may be the best therapeutic approach in the current scenario. © 2022 International Journal of Pharmaceutical Sciences and Nanotechnology. All right reserved.

In Silico Screening of Plant-Derived Anti-virals from Shorea hemsleyana (King) King ex Foxw Against SARS CoV-2 Main Protease

Shorea hemsleyana (King) King ex Foxw is used to treat various ailments in humans. Numerous biological activities have been reported previously. The current study sought to identify S. hemsleyana phyto-derived anti-viral compounds against the SARS-CoV-2 main protease to gain insight into the molecular interactions. In the present research, nine compounds obtained from the PubChem database are examined via molecular docking. Docking experiments were conducted using the AutoDock Vina tool. The Swiss ADME and DruLito servers were used for drug-like predictions. Our research shows that the phytoconstituents of S. hemsleyana, namely, Hemsleyanol-A and Hemsleyanoside-A, may act against SARS CoV-2 main protease with the binding affinity of - 7.6 and - 6.8 kcal/mol respectively, which were further validated by molecular dynamics (MD) simulations and end-state binding energy calculations. These phytocompounds could be used in contemporary strategies to develop effective medicines from natural sources. The identified substances are potential anti-viral agents. However, in vitro studies are necessary to assess their effectiveness against SARS-CoV-2.

Benchmarked molecular docking integrated molecular dynamics stability analysis for prediction of SARS-CoV-2 papain-like protease inhibition by olive secoiridoids.

Objectives: We performed a virtual screening of olive secoiridoids of the OliveNetTM library to predict SARS-CoV-2 PLpro inhibition. Benchmarked molecular docking protocol that evaluated the performance of two docking programs was applied to execute virtual screening. Molecular dynamics stability analysis of the top-ranked olive secoiridoid docked to PLpro was also carried out. Methods: Benchmarking virtual screening used two freely available docking programs, AutoDock Vina 1.1.2. and AutoDock 4.2.1. for molecular docking of olive secoiridoids to a single PLpro structure. Screening also included benchmark structures of known active and decoy molecules from the DEKOIS 2.0 library. Based on the predicted binding energies, the docking programs ranked the screened molecules. We applied the usual performance evaluation metrices to evaluate the docking programs using the predicted ranks. Molecular dynamics of the top-ranked olive secoiridoid bound to PLpro and computation of MM-GBSA energy using three iterations during the last 50 ps of the analysis of the dynamics in Desmond supported the stability prediction. Results and discussions: Predictiveness curves suggested that AutoDock Vina has a better predictive ability than AutoDock, although there was a moderate correlation between the active molecules rankings (Kendall's correlation of rank (τ) = 0.581). Interestingly, two same molecules, Demethyloleuropein aglycone, and Oleuroside enriched the top 1 % ranked olive secoiridoids predicted by both programs. Demethyloleuropein aglycone bound to PLpro obtained by docking in AutoDock Vina when analyzed for stability by molecular dynamics simulation for 50 ns displayed an RMSD, RMSF<2 Å, and MM-GBSA energy of -94.54 ± 6.05 kcal/mol indicating good stability. Molecular dynamics also revealed the interactions of Demethyloleuropein aglycone with binding sites 2 and 3 of PLpro, suggesting a potent inhibition. In addition, for 98 % of the simulation time, two phenolic hydroxy groups of Demethyloleuropein aglycone maintained two hydrogen bonds with Asp302 of PLpro, specifying the significance of the groups in receptor binding. Conclusion: AutoDock Vina retrieved the active molecules accurately and predicted Demethyloleuropein aglycone as the best inhibitor of PLpro. The Arabian diet consisting of olive products rich in secoiridoids benefits from the PLpro inhibition property and reduces the risk of viral infection.

Phytochemical Analysis, Antimutagenic and Antiviral Activity of Moringa oleifera L. Leaf Infusion: In Vitro and In Silico Studies.

Moringa oleifera (M. oleifera) leaves are rich in nutrients and antioxidant compounds that can be consumed to prevent and overcome malnutrition. The water infusion of its leaf is the easiest way to prepare the herbal drink. So far, no information is available on the antioxidant, antimutagenic, and antivirus capacities of this infusion. This study aimed to determine the composition of the bioactive compounds in M. oleifera leaf infusion, measuring for antioxidant and antimutagenic activity, and evaluating any ability to inhibit the SARS-CoV-2 main protease (Mpro). The first two objectives were carried out in vitro. The third objective was carried out in silico. The phytochemical analysis of M. oleifera leaf infusion was carried out using liquid chromatography-mass spectrometry (LC-MS). Antioxidant activity was measured as a factor of the presence of the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The antimutagenicity of M. oleifera leaf powder infusion was measured using the plasmid pBR322 (treated free radical). The interaction between bioactive compounds and Mpro of SARS-CoV-2 was analyzed via molecular docking. The totals of phenolic compound and flavonoid compound from M. oleifera leaf infusion were 1.780 ± 5.00 µg gallic acid equivalent/g (µg GAE/g) and 322.91 ± 0.98 µg quercetin equivalent/g (µg QE/g), respectively. The five main bioactive compounds involved in the infusion were detected by LC-MS. Three of these were flavonoid glucosides, namely quercetin 3-O-glucoside, kaempferol 3-O-neohesperidoside, and kaempferol 3-α-L-dirhamnosyl-(1→4)-ß-D-glucopyranoside. The other two compounds were undulatoside A, which belongs to chromone-derived flavonoids, and gentiatibetine, which belongs to alkaloids. The antioxidant activity of M. oleifera leaf infusion was IC50 8.19 ± 0.005 µg/mL, which is stronger than the standard butylated hydroxytoluene (BHT) IC50 11.60 ± 0.30 µg/mL. The infusion has an antimutagenic effect and therefore protects against deoxyribonucleic acid (DNA) damage. In silico studies showed that the five main bioactive compounds have an antiviral capacity. There were strong energy bonds between Mpro molecules and gentiatibetine, quercetin, undulatoside A, kaempferol 3-o-neohesperidoside, and quercetin 3-O-glucoside. Their binding energy values are -5.1, -7.5, -7.7, -5.7, and -8.2 kcal/mol, respectively. Their antioxidant activity, ability to maintain DNA integrity, and antimutagenic properties were more potent than the positive controls. It can be concluded that leaf infusion of M. oleifera does provide a promising herbal drink with good antioxidant, antimutagenic, and antivirus capacities.

Computational Prediction of Cassia angustifolia Compounds as a potential Drug Agents against Main Protease of SARS-nCov2

Background: In November-December 2019, a plethora of pneumonia like cases were reported in Wuhan, China. After some time, the causative agent of this ailment was identified and named as a novel coronavirus 2. This novel virus spread over the world with no time and declared as pandemic by WHO. To develop antiviral drugs, different clinically used drugs were used as a trial but went in vain. In the current study, we choose an herb with already known therapeutic effects to check its antiviral properties against this virus too. Methods: Cassia angustifolia is a well-known herb for pharmaceutical industries as its different compounds are already used in different medicines. Here we performed molecular docking of main compounds of Cassia angustifolia against the main protease of SARS-nCoV2 and were compared with different drugs that are already being used on commercial bases to obtain the lowest energy complex. Auto-Dock vina and its packages were used for molecular docking of SARS-nCov2. Results: Molecular docking of Cassia angustifolia compounds represent very promising binding energies complexes, e.g., Sennoside B gives -9.05kcal/mol and Aloe-Emodin give -4 Kcal/mol of energy against the main protease of coronavirus. In contrast, a couple of commercially used antiviral drugs were also evaluated against the selected protein of coronavirus e.g., Hydroxychloroquine and Ribavirin complexes appeared with -5.2 Kcal/mol and -6.3 Kcal/mol of energy respectively. Conclusion: Many compounds of Cassia angustifolia showed the promising energy complexes even better than the commercially used antiviral drugs e.g., Sennoside B which has the best energies against main protease of coronavirus. Further, in-vivo and in-vitro studies are needed to validate this hypothesis with advanced MD simulations and wet-lab experimentations.

Discovering the potential of natural remedies in the post COVID-19 complications based on in silico techniques

The first incidence of corona virus was reported in China in December of 2019, and the virus quickly spread over the world, eventually being designated a pandemic in March of 2020. It has had a disastrous impact on the global healthcare system. Virus has claimed the lives of 5,298,933 people through December 2021. As a result of the pandemic, there was a boost of research into diagnostic and therapeutic methods to infection. Gradually, the world has discovered new vaccine candidates and medicinal repurposing strategies that have a significant influence on mortality, by which there has been a drop-in death rates over the world since July, 2021. Many patients, particularly those who have been hospitalized due to a viral infection, experience complications beyond discharge that have a significant influence on their lives. Post COVID-19 complications are problems that last longer than 3-4 weeks following a viral infection. There is currently no specific treatment accessible for post COVID-19 problems because whatever medications are available or repurposed are limited to disease prophylaxis and therapeutics. As a result, we're looking for a remedy employing natural substances using the In-Silico technique (molecular docking) and recent research from reputable journals. Allicin, Berberine, Epigallocatechin, Rosmarinic acid and Withaferin-A were docked against ACE (PDB ID: 1O8A), IL-6 (PDB ID: 1ALU), NADPH Oxidase (PDB ID: 2CDU) and TNF-alpha (PDB ID: 2AZ5) using Autodock.

Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol-1, 6LU7 - 6.5 kcal mol-1, 6M3M - 5.8 kcal mol-1). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3.

Machine learning prediction of 3CLpro SARS-CoV-2 docking scores.

Molecular docking results of two training sets containing 866 and 8,696 compounds were used to train three different machine learning (ML) approaches. Neural network approaches according to Keras and TensorFlow libraries and the gradient boosted decision trees approach of XGBoost were used with DScribe's Smooth Overlap of Atomic Positions molecular descriptors. In addition, neural networks using the SchNetPack library and descriptors were used. The ML performance was tested on three different sets, including compounds for future organic synthesis. The final evaluation of the ML predicted docking scores was based on the ZINC in vivo set, from which 1,200 compounds were randomly selected with respect to their size. The results obtained showed a consistent ML prediction capability of docking scores, and even though compounds with more than 60 atoms were found slightly overestimated they remain valid for a subsequent evaluation of their drug repurposing suitability.

Evaluation of bioactive compounds from Boswellia serrata against SARS-CoV-2.

With the COVID-19 pandemic still wreaking havoc worldwide, new variants being discovered every month in some parts of the globe due to the mutating nature of the virus. There is no specific solution for this highly transmissible disease. In search of a lead molecule for the discovery and development of drug, extensive research is being conducted throughout the world. Many synthetic drugs are already in clinical trials and some are utilized for the treatment of this viral infection. Apart from synthetic drugs, phytocompounds from plants act as a potential drug candidate which can inhibit the growth of virus and thus able to prevent the viral infection. In this study, 26 ligands (bioactive compounds) from Boswellia serrata (an important medicinal plant) were tested against SARS-CoV-2 by using computational method. Selected ligands were shortlisted using Lipinski's rule and then subjected to molecular docking against one of the main proteins of SARS-CoV-2, i.e., Mpro. Out of these compounds, Euphane, Ursane, α-Amyrin, Phytosterols, and 2,3-Dihydroxyurs-12-en-28-oic acid were potential to inhibit the Mpro activity with binding energies of - 10.47 kcal/mol, - 10.41 kcal/mol, - 9.99 kcal/mol, - 9.94 kcal/mol and - 9.72 kcal/mol respectively. A comparative study was performed using the best five ligands against four possible drug targets of SARS-CoV-2. It was found that Euphane showed highest negative binding energy against all the four crucial targets of SARS-CoV-2. Further, in-vitro experimentation is required to validate the use of Euphane as a potent drug against SARS-CoV-2.

Nigellidine (Nigella sativa, black-cumin seed) docking to SARS CoV-2 nsp3 and host inflammatory proteins may inhibit viral replication/transcription and FAS-TNF death signal via TNFR 1/2 blocking.

Tissue damage occurs in COVID-19 patients due to nsp3-induced Fas-FasL interaction/TNF-related apoptosis. Presently, possible therapeutic-drug, nigellidine against was screened by bioinformatics studies COVID-19. Atomic-Contact-Energy (ACE) and binding-blocking effects were explored of nigellidine (Nigella sativa L.) in the active/catalytic sites of viral-protein nsp3 and host inflammatory/apoptotic signaling-molecules Fas/TNF receptors TNFR1/TNFR2. A control binding/inhibition of Oseltamivir to influenza-virus neuraminidase was compared here. In AutoDock, Oseltamivir binding-energy (BE) and inhibition-constant (KI) was -4.12 kcal/mol and 959.02. The ACE values (PatchDock) were -167.02/-127.61/-124.91/-122.17/-54.81/-47.07. The nigellidine BE/KI with nsp3 was -7.61 and 2.66, respectively (ACE values were -221.40/-215.62/-113.28). Nigellidine blocked FAS dimer by binding with a BE value of -7.41 kcal/mol. Its strong affinities to TNFR1 (-6.81) and TNFR2 (-5.1) are demonstrated. Our present data suggest that nigellidine may significantly block the TNF-induced inflammatory/Fas-induced apoptotic death-signaling in comparison with a positive-control drug Oseltamivir. Further studies are necessary before proposing nigellidine as medical drug.

Virtual screening, drug-likeness analysis, and molecular docking study of potential severe acute respiratory syndrome coronavirus 2 main protease inhibitors

Due to the length of time required to develop specific antiviral agents, the World Health Organization adopted the strategy of repurposing existing medications to treat Coronavirus disease 2019 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease is possible biological target for potential antiviral drugs. We selected various compounds from PubChem database based on the structure of main protease inhibitors in Protein Data Bank database. Ten compounds showed nontumorigenic and nonmutagenic potential and met Egan's and Lipinski's rules. Molecular docking analysis was performed using AutoDock Vina software. Based on number and type of key binding interactions, as well as docking scores, we selected compounds 6, 8, and 17 that demonstrated the highest binding affinity for the target protein. Molecular dynamics simulations were then carried out on the protein-top docked ligand complexes which were subjected to Molecular mechanics/generalized Born and surface area calculations. The molecular dynamics simulation results indicated that protein-top docked ligand complexes showed good conformational stability. Among analyzed molecules, compound 17 emerged as the best in silico hit based on the docking score, MM/GBSA binding energy and MD results.

In silico identification of potential inhibitors from Cinnamon against main protease and spike glycoprotein of SARS CoV-2.

Cinnamon has been utilized to remedy a lot of afflictions of humans. Literary works illustrate that it possesses numerous biological activities. Our research study is intended to recognize the phyto-derived antiviral substances from Cinnamon against COVID-19 main protease enzyme and to understand the in silico molecular basis of its activity. In the present study, 48 isolates compounds from Cinnamon retrieved from the PubMed database, are subjected to docking analysis. Docking study was performed using Autodock vina and PyRx software. Afterwards, admetSAR, as well as DruLiTo servers, were used to investigate drug-likeness prophecy. Our study shows that the nine phytochemicals of Cinnamon are very likely against the main protease enzyme of COVID-19. Further MD simulations could identify Tenufolin (TEN) and Pavetannin C1 (PAV) as hit compounds. Utilizing contemporary strategies, these phyto-compounds from a natural origin might establish a reliable medication or support lead identification. Identified hit compounds can be further taken for in vitro and in vivo studies to examine their effectiveness versus COVID-19.

Investigating Fungi-Derived Bioactive Molecules as Inhibitor of the SARS Coronavirus Papain Like Protease: Computational Based Study.

Due to the rapid growth of the COVID-19 pandemic and its outcomes, developing a remedy to fight the predicament is critical. So far, it has infected more than 214,468,601 million people and caused the death of 4,470,969 million people according to the August 27, 2021, World Health Organization's (WHO) report. Several studies have been published on both computational and wet-lab approaches to develop antivirals for COVID-19, although there has been no success yet. However, the wet-lab approach is laborious, expensive, and time-consuming, and computational techniques have screened the activity of bioactive compounds from different sources with less effort and cost. For this investigation, we screened the binding affinity of fungi-derived bioactive molecules toward the SARS coronavirus papain-like protease (PLpro) by using computational approaches. Studies showed that protease inhibitors can be very effective in controlling virus-induced infections. Additionally, fungi represent a vast source of bioactive molecules, which could be potentially used for antiviral therapy. Fifty fungi-derived bioactive compounds were investigated concerning SARS-CoV-2 PLpro by using Auto Dock 4.2.1, Gromacs 2018. 2, ADMET, Swiss-ADME, FAF-Drugs 4.023, pKCSM, and UCLA-DOE server. From the list of the screened bioactive compounds, Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin were selected with the Auto-Dock results of -8.68, -7.52, -10.46, and -10.58 Kcal/mol, respectively, based on their binding affinity compared to the reference drug. We presented the drug likeliness, toxicity, carcinogenicity, and mutagenicity of all compounds using ADMET analysis. They interacted with the amino acid residues, Gly163, Trp106, Ser111, Asp164, and Cys270, through hydrogen bonds. The root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg) values revealed a stable interaction. From the overall analyses, we can conclude that Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin are classified as promising candidates for PLpro, thus potentially useful in developing a medicine for COVID-19.