In silico identification of new anti-SARS-CoV-2 agents from bioactive phytocompounds targeting the viral spike glycoprotein and human TLR4

2021 ◽  
Vol 18 ◽  
Author(s):  
Nabarun Chandra Das ◽  
Rajendra Kumar Labala ◽  
Ritwik Patra ◽  
Asamanja Chattoraj ◽  
Suprabhat Mukherjee
Keyword(s):  
In Silico ◽  
Md Simulation ◽  
Docking Study ◽  
Spike Glycoprotein ◽  
Molecular Docking Study ◽  
S Protein ◽  
Proinflammatory Responses ◽  
Experimental Validations ◽  
The Stability ◽  
Novel Coronavirus

Background: The recent outbreak of novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 has posed a tremendous threat to mankind. The unavailability of a specific drug or vaccine has been the major concern to date. Spike (S) glycoprotein of SARS-CoV-2 plays the most crucial role in the viral infection and immunopathogenesis, and hence this protein appears to be an efficacious target for drug discovery. Objective: Identifying potent bioactive phytocompound that can target viral spike (S) glycoprotein and human TLR4 to reduce immunopathological manifestations of COVID-19. Method: A series of thirty (30) bioactive phytocompounds, previously documented for antiviral activity, were theoretically screened for their binding efficacy against key proteins related to pathogenesis of SARSCoV-2 namely viral spike (S) glycoprotein and human TLR4. MD simulation was employed to verify the postulations of molecular docking study and further ADME analysis was performed to predict the most effective one. Results: Studies hypothesized that two new phytochemicals viz. cajaninstilbene acid (-8.83 kcal/mol) and papaverine (-5.81 kcal/mol) might be the potent inhibitors of spike glycoprotein with stout binding affinity and favourable ADME attributes. MD simulation further ratified the stability of the docked complexes between the phytochemicals and S protein through strong hydrogen bonding. Our in silico data also indicated that cajaninstilbene acid and papaverine might block human TLR4 which could be useful to mitigate SARS-CoV-2-induced lethal proinflammatory responses. Conclusion: Experimental data collectively predict cajaninstilbene acid as the potential blocker of S protein which may be used as anti-viral against COVID-19 in the future. However, further experimental validations alongside toxicological detailing are needed for claiming the candidature of these molecules as future anti-corona therapeutics.

scholarly journals Gymnema Sylvestre A- Potential Inhibitor of COVID-19 Main Protease by MD Simulation Study

2020 ◽  
Author(s):  
Senthil Kumar Subramani ◽  
Yash Gupta ◽  
Manish Manish ◽  
GBKS Prasad
Keyword(s):  
Md Simulation ◽  
Docking Study ◽  
Binding Pocket ◽  
Gymnema Sylvestre ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Strong Candidate ◽  
The Stability ◽  
Potential Inhibitors ◽  
Domain I

Gymnema sylvestre (GS) is one of the herbal plant used since in ancient times. The present study aimed to assess bioactive compounds GS mainly gymnemic acids as potential inhibitors for COVID-19 against Mpro enzyme using a molecular docking study. The docking score observed between -53.4 to - 42.4 of all gymnemic acids and its derivatives. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of GS molecules within the binding pocket. RMSD score of less than 3.6. mainly, our results supported that these GS molecules bind to the domain I & II, and domain II-III linker of 3CLpro enzyme, suggesting its suitability as strong candidate for therapeutic against COVID-19. <br>

scholarly journals Pharmacoinformatics-based investigation of bioactive compounds of Rasam (South Indian recipe) against human cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arjun Kumar Kalimuthu ◽  
Theivendren Panneerselvam ◽  
Parasuraman Pavadai ◽  
Sureshbabu Ram Kumar Pandian ◽  
Krishnan Sundar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bioactive Compounds ◽  
In Silico ◽  
Md Simulation ◽  
Human Cancer ◽  
Binding Energies ◽  
Mitogen Activated Protein Kinase ◽  
Molecular Docking Study ◽  
South Indian ◽  
The Stability

AbstractSpice-rich recipes are referred to as “functional foods” because they include a variety of bioactive chemicals that have health-promoting properties, in addition to their nutritional value. Using pharmacoinformatics-based analysis, we explored the relevance of bioactive chemicals found in Rasam (a South Indian cuisine) against oxidative stress-induced human malignancies. The Rasam is composed of twelve main ingredients, each of which contains a variety of bioactive chemicals. Sixty-six bioactive compounds were found from these ingredients, and their structures were downloaded from Pubchem. To find the right target via graph theoretical analysis (mitogen-activated protein kinase 6 (MAPK6)) and decipher their signaling route, a network was built. Sixty-six bioactive compounds were used for in silico molecular docking study against MAPK6 and compared with known MAPK6 inhibitor drug (PD-173955). The top four compounds were chosen for further study based on their docking scores and binding energies. In silico analysis predicted ADMET and physicochemical properties of the selected compounds and were used to assess their drug-likeness. Molecular dynamics (MD) simulation modelling methodology was also used to analyse the effectiveness and safety profile of selected bioactive chemicals based on the docking score, as well as to assess the stability of the MAPK6-ligand complex. Surprisingly, the discovered docking scores against MAPK6 revealed that the selected bioactive chemicals exhibit varying binding ability ranges between − 3.5 and − 10.6 kcal mol−1. MD simulation validated the stability of four chemicals at the MAPK6 binding pockets, including Assafoetidinol A (ASA), Naringin (NAR), Rutin (RUT), and Tomatine (TOM). According to the results obtained, fifty of the sixty-six compounds showed higher binding energy (− 6.1 to − 10.6 kcal mol−1), and four of these compounds may be used as lead compounds to protect cells against oxidative stress-induced human malignancies.

scholarly journals In Silico Identification of Potential Therapeutic Agents for COVID-19 Based on Molecular Docking Study of Main Protease and Receptor Binding Domain of Spike Protein.

2021 ◽  
Author(s):  
Vajiheh Eskandari
Keyword(s):  
Folic Acid ◽  
Receptor Binding ◽  
In Silico ◽  
Docking Study ◽  
Binding Domain ◽  
Dynamics Simulation ◽  
Receptor Binding Domain ◽  
Active Site Residues ◽  
Molecular Docking Study ◽  
S Protein

Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV-2) enter the cell by interacting with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. In the cell the viral 3-chymotrypsin-like cysteine protease (3CLp) enzyme is essential for its life cycle and controls coronavirus replication. Therefore the S-RBD and 3CLp are hot targets for drugs discovery against SARS-CoV-2. This study was to identify repurposing drugs using in-silico screening, docking and molecular dynamics simulation. The study identified Dibenzoyl Thiamine, Folic Acid and Vitamin B12 against the RBD of S-protein and Dibenzoyl Thiamine, Folic Acid, Fursultiamine and Riboflavin to 3CLp. The strong and stable binding of these safe and cheap vitamins at the important residues (R403, K417, Y449, Y453, N501 and Y505) in S-protein –ACE2 interface and 3CLp active site residues (His 41 and Cys 145), indicating that they could be valuable repurpose drugs for inhibiting SARS-CoV-2 entry into the host and replication.

In silico screening of FDA approved drugs predicts the therapeutic potentials of Antibiotic drugs against the papain like protease of SARS-CoV-2

2021 ◽  
pp. 4035-4039
Author(s):  
Vipul Kumar ◽  
Sudhakar Kancharla ◽  
Manoj Kumar Jena
Keyword(s):  
In Silico ◽  
Computational Study ◽  
Docking Study ◽  
Wild Type ◽  
In Silico Screening ◽  
Antibiotic Drugs ◽  
Experimental Validations ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Fda Approved Drugs

Since the outbreak of severe acute respiratory syndrome corona Virus -2 (SARS-CoV-2) has happened in December 2019 in Wuhan, China, the cases of novel coronavirus disease (COVID-19) is rapidly increasing worldwide. In the absence of specific drugs against COVID-19, the fast and reliable choice would be repurposing of existing drugs. Here, we have chosen one of the crucial enzymes of the SARS-CoV-2, Papain like protease (PLpro) and its mutant C111S for the structure-based in-silico screening of the FDA approved drugs. Firstly, the alignment of the wild type and mutant PLpro was done, and no significant change in the global structure was observed. Then based on the docking study, we have reported the best 3 compounds against a mutant and wild type PLpro. These lead compounds include amikacin and mafenide, which are well-known antibiotics. The binding affinity, as well as number of polar and non-polar interactions, indicates their potential against the PLpro. This computational study strongly suggests the experimental validations of the predicted compounds for a confident claim.

scholarly journals SARS-COV-2 Spike Glycoprotein as Inhibitory Target for In silico Screening of Natural Compounds

2021 ◽  
Vol 11 (6) ◽  
pp. 14974-14985
Keyword(s):  
In Silico ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Spike Glycoprotein ◽  
Life Threatening ◽  
Inhibitory Potential ◽  
The Stability ◽  
Approved Drugs

Coronavirus disease (Covid-19) caused by SARS-Cov-2 has raised global health concerns without approved drugs to manage this life-threatening disease. This study aimed to predict the inhibitory potential of quercetin-3-o-rutinoside against SARS-Cov-2 spike glycoprotein. Targeting the SARS-Cov-2 Nucleocapsid spike glycoprotein (pdb id: 6m3m) is gaining importance. In this present study, the relationship between plant-derived natural drug and spike glycoprotein was predicted using in silico computational approach. The results were evaluated according to the glide (Schrodinger) dock score. Among the five (5) screened natural compounds, quercetin-3-o-rutinoside has the best docking score (-9.296) with the target. Molecular dynamic (MD) simulation analysis was performed for 1000ps to confirm the spike protein's stability behavior and quercetin-3-o-rutinoside complex. The MD simulation analysis validated the stability of quercetin-3-o-rutinoside in the spike protein binding pocket as a potent inhibitor. The pharmacokinetics screening of the natural compounds showed that quercetin-3-o-rutinoside possesses good oral bioavailability with no side effects.

scholarly journals Gymnema Sylvestre A- Potential Inhibitor of COVID-19 Main Protease by MD Simulation Study

2020 ◽  
Author(s):  
Senthil Kumar Subramani ◽  
Yash Gupta ◽  
Manish Manish ◽  
GBKS Prasad
Keyword(s):  
Md Simulation ◽  
Docking Study ◽  
Binding Pocket ◽  
Gymnema Sylvestre ◽  
Molecular Docking Study ◽  
Main Protease ◽  
Strong Candidate ◽  
The Stability ◽  
Potential Inhibitors ◽  
Domain I

Gymnema sylvestre (GS) is one of the herbal plant used since in ancient times. The present study aimed to assess bioactive compounds GS mainly gymnemic acids as potential inhibitors for COVID-19 against Mpro enzyme using a molecular docking study. The docking score observed between -53.4 to - 42.4 of all gymnemic acids and its derivatives. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of GS molecules within the binding pocket. RMSD score of less than 3.6. mainly, our results supported that these GS molecules bind to the domain I & II, and domain II-III linker of 3CLpro enzyme, suggesting its suitability as strong candidate for therapeutic against COVID-19. <br>

EVALUATION OF IN-SILICO ANTICANCER POTENTIAL OF PYRETHROIDS: A COMPARATIVE MOLECULAR DOCKING STUDY

2015 ◽  
Author(s):  
Manik Ghosh ◽  
Kamal Kant ◽  
Anoop Kumar ◽  
Padma Behera ◽  
Naresh Rangra ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Study ◽  
Molecular Docking Study

Computational Evidences of Phytochemical Mediated Disruption of PLpro Driven Replication of SARS-CoV-2: A Therapeutic Approach Against COVID-19

2020 ◽  
Vol 21 ◽  
Author(s):  
Acharya Balkrishna ◽  
Rashmi Mittal ◽  
Vedpriya Arya
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Bond Distance ◽  
Immunological Response ◽  
Docking Study ◽  
Receptor Interaction ◽  
Molecular Docking Study ◽  
Replication Process ◽  
Stable Conformation ◽  
Distance Analysis

Background:: COVID-19 caused by SARS-CoV-2 has been declared as global pandemic by WHO. Comprehensive analysis of this unprecedented outbreak may help to fight against the disease and may play a pivotal role in decreasing the mortality rate linked with it. Papain like protease (PLpro), a multifunctional polyprotein facilitates the replication of SARS-CoV-2 and evades it from the host immunological response by antagonizing cytokines, interferons and may be considered as potential drug target to combat the current pandemic. Methods:: Natural moieties obtained from medicinal plants were analysed for their potency to target PLpro of SARS-CoV-2 by molecular docking study and were compared with synthetic analogs named as remdesivir, chloroquine and favipiravir. The stability of complexes of top hits was analysed by MD Simulation and interaction energy was calculated. Furthermore, average RMSD values were computed and deepsite ligand binding pockets were predicted using Play Molecule. Drug like abilities of these moieties were determined using ADMET and bond distance between the ligand and active site was assessed to predict the strength of interaction. Results:: Nimbocinol (-7.6 Kcal/mol) and sage (-7.3 Kcal/mol) exhibited maximum BA against PLpro SARS-CoV-2 as evident from molecular docking study which was found to be even better than remdesivir (-6.1 Kcal/mol), chloroquine (-5.3 Kcal/mol) and favipiravir (-5.7 Kcal/mol). Both nimbocinol-PLpro and sage-PLpro SARS-CoV-2 complex exhibited stable conformation during MD Simulation of 101ns at 310 K and potential, kinetic and electrostatic interaction energies were computed which was observed to be concordant with results of molecular docking study. RMSD average values were found to be 0.496 ± 0.015 Å and 0.598 ± 0.023 Å for nimbocinol and sage respectively thus revealing that both the deviation and fluctuations during MD Simulation were observed to be least. Deepsite prediction disclosed that both compounds occupied cryptic pockets in receptor and non-bond distance analysis revealed the formation of hydrogen bonds during ligand-receptor interaction. ADMET exploration further validated the drug like properties of these compounds. Conclusion:: Present study revealed that active constituents of Azadirachta indica and Salvia officinalis can be potentially used to target SARS-CoV-2 by hindering its replication process.

Synthesis, SAR, In-Silico appraisal and Anti-Microbial Study of substituted 2-aminobenzothiazoles derivatives

2019 ◽  
Vol 15 ◽  
Author(s):  
Devidas G. Anuse ◽  
Suraj N. Mali ◽  
Bapu R. Thorat ◽  
Ramesh S. Yamgar ◽  
Hemchandra K. Chaudhari
Keyword(s):  
Antimicrobial Activity ◽  
In Silico ◽  
Docking Study ◽  
Moderate Activity ◽  
Molecular Docking Study ◽  
Mass Spectral ◽  
Gram Positive Bacteria ◽  
Ft Ir ◽  
In Silico Molecular Docking

Background: Antimicrobial resistance is major global health problem, which is being rapidly deteriorating the quality of human health. Series of substituted N-(benzo[d]thiazol-2-yl)-2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)acetamide (3a-j) were synthesized from substituted N-(benzo[d]thiazol-2-yl)-2-chloroacetamide/bromopropanamide (2a-j) and 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (2) and further evaluated for their docking properties and antimicrobial activity. Methods: All synthesized compounds were characterized by FT-IR, NMR and Mass spectral analysis. All compounds were allowed to dock against different antimicrobial targets having PDB ID: 1D7U and against common antifungal target having PDB ID: 1EA1. Results: The compounds 3d and 3h were showed good activity against Methicillin-resistant Staphylococcus aureus (MRSA, resistance Gram-positive bacteria). All synthesized compounds showed good to moderate activity against selected bacterial and fungal microbial strains. If we compared the actual in-vitro antimicrobial activity and in-silico molecular docking study, we found that molecules 3i and 3h were more potent than the others. Conclusion: Our current study would definitely pave the new way towards designing and synthesis of more potent 2-aminobenzothiazoles derivatives.

Synthesis, Biological Evaluation and Molecular Docking Study of Cyclic Diarylheptanoids as Potential Anticancer Therapeutics

2020 ◽  
Vol 20 (4) ◽  
pp. 464-475 ◽  
Author(s):  
Yang Lu ◽  
Wencui Yin ◽  
Mohammad S. Alam ◽  
Adnan A. Kadi ◽  
Yurngdong Jahng ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
In Silico ◽  
Topoisomerase I ◽  
Biological Activities ◽  
Cancer Cell Line ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Topoisomerase Iiα ◽  
Inhibitory Activities ◽  
Formed Hydrogen

Background: Cancer is one of the leading causes of mortality globally. To cope with cancer, it is necessary to develop anticancer drugs. Bioactive natural products, i.e. diarylheptanoids, have gained significant attention of researchers owing to their intriguing structures and potent biological activities. In this article, considering the development of anticancer drugs with enhanced selectivity towards cancerous cells, a series of Cyclic Diarylheptanoids (CDHs) are designed, synthesized and evaluated their biological activity. Objective: To establish an easy route for the synthesis of diarylheptanoids, and evaluate their antiproliferative, and topoisomerase-I & -IIα inhibitory activities, for developing potential anticancer drugs among CDHs. Methods: Diarylheptanoids were synthesized from reported linear diarylheptanoids using the classical Ullmann reaction. Antibacterial activity was evaluated by the filter paper disc diffusion method. Cell viability was assessed by measuring mitochondrial dehydrogenase activity with a Cell Counting Kit (CCK-8). Topoisomerases I and II (topo-I and -IIα) inhibitory activity was measured by the assessment of relaxation of supercoiled pBR322 plasmid DNA. IFD protocol of Schrodinger Maestro v11.1 was used to characterize the binding pattern of studied compounds with the ATPase domain of the human topo-IIα. Results: The synthesized CDHs were evaluated for their biological activities (antibacterial, antiproliferative, and topoisomerase-I & -IIα inhibitory activities, respectively). Leading to obtain a series of anticancer agents with the least inhibitory activities against different microbes, improving their selectivity for cancer cells. In brief, most of the synthesized CDHs had excellent antiproliferative activity against T47D (human breast cancer cell line). Pterocarine possessed the strongest activity (2i; IC50 = 0.63µM) against T47D. The cyclic diarylheptanoid 2b induced 30% inhibition of topoisomerase-IIα activity at 100μM compared with the reference of etoposide, which induced 72% inhibition. Among the tested compounds, galeon (2h) displayed very low activity against four bacterial strains. Compounds 2b, 2h, and 2i formed hydrogen bonds with Thr215, Asn91, Asn120, Ala167, Lys168 and Ile141 residues, which are important for binding of ligand compound to the ATPase binding site of topoisomerase IIα by acting as ATP competitive molecule validated by docking study. In silico Absorption, Distribution, Metabolism and Excretion (ADME) analysis revealed the predicted ADME parameters of the studied compounds which showed recommended values. Conclusion: A series of CDHs were synthesized and evaluated for their antibacterial, antiproliferative, and topo-I & -IIα inhibitory activities. SARs study, molecular docking study and in silico ADME analysis were conducted. Five compounds exhibited excellent and selective antiproliferative activity against the human breast cancer cell line (T47D). Among them, a compound 2h showed topo-IIα activity by 30% at 100µM, which represented a moderate intensity of inhibition compared with etoposide. Three of them formed hydrogen bonds with Thr215, Asn91, Asn120, and Ala167 residues, which are considered as crucial residues for binding to the ATPase domain of topoisomerase IIα. According to in silico drug-likeness property analysis, three compounds are expected to show superiority over etoposide in case of absorption, distribution, metabolism and excretion.

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