scholarly journals In silico approach: Anthocyanin derivatives as potential inhibitors of the COVID-19 main protease

2020 ◽  
Author(s):  
Muhammad Ikhlas Abdjan ◽  
Khusna Arif Rakhman ◽  
Sri Handayani ◽  
Chairil Anjasmara Robo Putra ◽  
Imam Siswanto
Keyword(s):  
In Silico ◽  
Binding Free Energy ◽  
Solvent Accessibility ◽  
Geometry Optimization ◽  
Initial Step ◽  
System Stability ◽  
Drug Candidates ◽  
Main Protease ◽  
Reference Ligand ◽  
Type Studies

In silico approach has been carried out for the determination of drug candidates from anthocyanin derivative as inhibitors of the COVID-19 main protease. Geometry optimization has performed using the DFT/B3LYP/6-31G(d,p) method as an initial step to prepare candidate ligand. The results of molecular docking showed that candidates C5 and C6 had promising results with a grid score smaller than the ligand reference (X77) with a flexible conformation type. Studies on absorption, distribution, metabolism, excretion, and toxicity of C5 and C6 candidates were conducted to study the physicochemical properties of drug candidates and to show good predictive results as drugs. Molecular dynamic simulation uses the ffSB14 force field for 200 ns to study the interaction between ligand and receptor, the system stability, solvent accessibility, energy interactions, and hydrogen bonds. The results show good interaction stability on the C5 complex compared to the reference ligand which is characterized by the binding free energy value of C5 was -42.77 ± 0.37 kcal/mol and X77 was -42.37 ± 0.41 kcal/mol.

scholarly journals Identification of promising drug candidates against Non-Structural Protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing studies

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Ekampreet Singh ◽  
Monika Jain ◽  
Gizachew Muluneh Amera ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Therapeutic Agents ◽  
Global Dynamics ◽  
Host Immune System ◽  
Structural Protein ◽  
Drug Candidates

<div>The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The notorious nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an <i>in silico</i> based drug repurposing approach to identify potential drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2</div><div>which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. NSP15 was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated free energy of binding (<i>ΔG</i>), estimated inhibition constant (<i>Ki</i>), the orientation of drug molecules in the active site and the key interacting residues of</div><div>NSP15. The MD simulations were performed for the selected NSP15-drug complexes along with free protein to mimic on their physiological state. The binding free energies of the selected NSP15-drug complexes were also calculated using the trajectories of MD simulations of NSP15-drug complexes through MM/PBSA (Molecular Mechanics with Poisson-Boltzmann and surface area solvation) approach where NSP15-Simeprevir (-242.559 kJ/mol) and NSP15-Paritaprevir (-149.557 kJ/mol) exhibited the strongest binding affinities. Together with the results of molecular docking, global dynamics, essential dynamics and binding free energy analysis, we propose that Simeprevir and Paritaprevir are promising drug candidates for the inhibition of NSP15 and could act as potential therapeutic agents against SARS-CoV-2.</div>

Activity of Thiazine substituted 9-anilinoacridines against Corona virus (COVID19): An In-silico approach

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 482-490
Author(s):  
Kalirajan Rajagopal ◽  
Potlapati Varakumar ◽  
Baliwada Aparna ◽  
Vulsi Bodhya Sri ◽  
Gowramma Byran ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Free Energy ◽  
Viral Disease ◽  
Docking Studies ◽  
Binding Modes ◽  
Main Protease ◽  
In Silico Admet ◽  
In Silico Studies ◽  
Life Threatening ◽  
Similar Mode

Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease affected first in Wuhan, China, and quickly spread to more than 200 countries in the world in the year 2020. So many scientists are trying to discover novel drugs and vaccines for coronavirus and treatment for COVID-19. In the present article, in-silico studies have been performed to explore the binding modes of Thiazine substituted 9-anilinoacridines (1a-z) against SARS CoV 2 main protease (PDB id - 5R82) targeting the coronavirus using Schrodinger suit 2019-4. The molecular docking studies are performed by Glide module, in-silico ADMET screening was performed by Qik prop module, and the binding free energy of ligands was calculated using PRIME MM-GB/SA module of Schrodinger suite 2019-4, Maestro 21.2 version. From the in-silico results, Thiazine substituted 9-anilinoacridines like 1m, 1j, 1s and 1b are significantly active against SARS CoV 2 main protease with Glide score more than -5.4 when compared with the currently recommended drug for COVID19, Hydroxychloroquine (G score -5.47). The docking results of the Thiazine substituted 9-anilinoacridines exhibited similar mode of interactions with COVID19 and the residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN142, GLN143, HIE164, MET165, ASP187, ARG188 and GLN189, play a crucial role in binding with ligands.

scholarly journals In Silico Prediction of Inhibitory Potential of a Punicalagin β-anomer Against SARS-COV-2 Main Protease (Mpro)

2021 ◽  
Author(s):  
Norberto Monteiro ◽  
Vitória Monteiro ◽  
Lorena Lima ◽  
Anna Karolline ◽  
Richele Machado
Keyword(s):  
Molecular Dynamics ◽  
In Silico ◽  
Treatment Strategies ◽  
Punica Granatum ◽  
Drug Candidate ◽  
Fruit Peel ◽  
Drug Candidates ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Inhibitory Potential

Abstract The pandemic caused by the new coronavirus has resulted in a global health emergency and has prompted an urgent need for new treatment strategies. No target-specific drugs are currently available for SARS-CoV-2, but new drug candidates targeting the viral replication cycle are being explored. A prime target of drug-discovery efforts is the SARS-CoV-2 main protease (Mpro). In this work, we identified a potential inhibitor for SARS-CoV-2 main protease using in silico methodologies. Molecular docking and molecular dynamics studies were carried out to ascertain the inhibitory action of α and β anomers of Punicalagin from fruit peel of Punica granatum against the Mpro protease. The molecular dynamics results revealed that the β-anomeric configuration of punicalagin allowed access to more hydrogen bonds and hydrophobic interaction leading to higher selectivity and specificity of β-anomer than α-anomer. Therefore, the β-anomer of Punicalagin could act as potential inhibitor against the main protease of SARS-CoV-2 and may act as a potential drug candidate.

scholarly journals Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)

2020 ◽  
Vol 8 (7) ◽  
pp. 970 ◽  
Author(s):  
Ahmed M. Sayed ◽  
Hani A. Alhadrami ◽  
Ahmed O. El-Gendy ◽  
Yara I. Shamikh ◽  
Lassaad Belbahri ◽  
...  
Keyword(s):  
Natural Products ◽  
Protein Complexes ◽  
Binding Free Energy ◽  
Binding Affinities ◽  
Binding Modes ◽  
Drug Candidates ◽  
Main Protease ◽  
Potential Inhibitors ◽  
Microbial Natural Products

The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski’s rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Final MDS experiments were performed on the ligand–protein complexes (compounds 1–12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1–6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.

scholarly journals Drug Repurposing to Identify Therapeutics Against COVID 19 with SARS-Cov-2 Spike Glycoprotein and Main Protease as Targets: An in Silico Study

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Sadasivan C
Keyword(s):  
In Silico ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Drug Candidates ◽  
Protein Receptor ◽  
Main Protease ◽  
In Silico Study ◽  
Molecular Modeling And Docking ◽  
Different Parts

<p>The total cases of novel corona virus (SARS-CoV-2) infections is more than one million and total deaths recorded is more than fifty thousand. The research for developing vaccines and drugs against SARS-CoV-2 is going on in different parts of the world. Aim of the present study was to identify potential drug candidates against SARS-CoV-2 from existing drugs using <i>in silico</i> molecular modeling and docking. The targets for the present study was the spike protein and the main protease of SARS-CoV-2. The study was able to identify some drugs that can either bind to the spike protein receptor binding domain or the main protease of SARS-CoV-2. These include some of the antiviral drugs. These drugs might have the potential to inhibit the infection and viral replication.</p>

scholarly journals Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

2020 ◽  
Author(s):  
chinmayee choudhury
Keyword(s):  
Binding Site ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Corona Virus ◽  
Main Protease ◽  
New Chemical Entities ◽  
Reference Ligand ◽  
Binding Cavity ◽  
Binding Pockets ◽  
Dynamics Simulations

<p></p><p>The recent pandemic of novel corona virus (nCoV) infections (COVID19) has put the world on serious alert. The main protease of nCov (nCov-MP) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the nCov-MP binding site. A huge library of 191678 fragments was screened against the binding cavity of nCov-MP and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET property filters and MM-GBSA binding free energy calculations to select 17 best molecules (named as MP-In1 to Mp-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with nCov-MP, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with nCov-MP. Fifteen molecules were found to form stable complexes with nCov-MP. These novel chemical entities designed specifically according to the pharmacophoric requirements of nCov-MP binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for nCov drug discovery. </p><br><p></p>

scholarly journals In silico Investigation of Tridax procumbens Phyto-Constituents Against SARS-CoV-2 Infection

2021 ◽  
Vol 11 (4) ◽  
pp. 12120-12148
Keyword(s):  
In Silico ◽  
Computational Analysis ◽  
Docking Studies ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Drug Candidates ◽  
Main Protease ◽  
Tridax Procumbens ◽  
Protection Profile ◽  
High Binding Affinity

Tridax procumbens is a popular medicinal plant traditionally used for wound healing and bronchial catarrh. In the current study, in silico computational analysis of 22 active phytoconstituents of T. procumbens was performed against SARS-CoV-2. Molecular Docking studies against six key targets of SARS-CoV-2 including PDB ID: 6LU7, a main protease 3CLpro/Mpro; PDB ID: 6NUR, SARS-Coronavirus NSP12 polymerase bound to NSP7 and NSP8 co-factors, PDB ID: 6m71, SARS-Cov-2 RNA-dependent RNA polymerase (RdRp), PDB ID: 6CS2, SARS Spike Glycoprotein - human ACE2 complex a Stabilized variant; PDB ID: 6VXX, spike glycoprotein of SARS-CoV-2 and its receptor Angiotensin-converting enzyme-2 (PDB ID: 1R42) were accomplished. Additionally, in silico prediction studies using pharmacokinetics (ADMET) properties and the protection profile to identify the paramount drug candidates were also done using online SwissADME and pkCSM web servers. Comprehensive docking analyses confirmed that out of 22 screened phytoconstituents, 6 compounds: Bergenin, beta-Sitosterol, Centaurein, Procumbentin, Luteolin, and Puerarin showed a high binding affinity with studied SARS-CoV-2 target proteins. Pharmacokinetics prediction studies further verified that all selected phytoconstituents were safe with good quality ADMET properties and lacking carcinogenic and tumorigenic properties. Thus, these selected drugs can effectively control COVID-19 and improve immunity, which can be confirmed by further studies.

scholarly journals Identification of promising drug candidates against Non-Structural Protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing studies

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Ekampreet Singh ◽  
Monika Jain ◽  
Gizachew Muluneh Amera ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Therapeutic Agents ◽  
Global Dynamics ◽  
Host Immune System ◽  
Structural Protein ◽  
Drug Candidates

<div>The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The notorious nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an <i>in silico</i> based drug repurposing approach to identify potential drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2</div><div>which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. NSP15 was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated free energy of binding (<i>ΔG</i>), estimated inhibition constant (<i>Ki</i>), the orientation of drug molecules in the active site and the key interacting residues of</div><div>NSP15. The MD simulations were performed for the selected NSP15-drug complexes along with free protein to mimic on their physiological state. The binding free energies of the selected NSP15-drug complexes were also calculated using the trajectories of MD simulations of NSP15-drug complexes through MM/PBSA (Molecular Mechanics with Poisson-Boltzmann and surface area solvation) approach where NSP15-Simeprevir (-242.559 kJ/mol) and NSP15-Paritaprevir (-149.557 kJ/mol) exhibited the strongest binding affinities. Together with the results of molecular docking, global dynamics, essential dynamics and binding free energy analysis, we propose that Simeprevir and Paritaprevir are promising drug candidates for the inhibition of NSP15 and could act as potential therapeutic agents against SARS-CoV-2.</div>

scholarly journals In Silico Modeling as a Perspective in Developing Potential Vaccine Candidates and Therapeutics for COVID-19

Coatings ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1273
Author(s):  
Reham Barghash ◽  
Iten Fawzy ◽  
Vaisali Chandrasekar ◽  
Ajay Singh ◽  
Uma Katha ◽  
...  
Keyword(s):  
In Silico ◽  
Computational Models ◽  
Vaccine Development ◽  
Antiviral Agents ◽  
Drug Candidates ◽  
Main Protease ◽  
In Silico Modeling ◽  
Potential Vaccine ◽  
Approved Drugs ◽  
New Strategies

The potential of computational models to identify new therapeutics and repurpose existing drugs has gained significance in recent times. The current ‘COVID-19′ pandemic caused by the new SARS CoV2 virus has affected over 200 million people and caused over 4 million deaths. The enormity and the consequences of this viral infection have fueled the research community to identify drugs or vaccines through a relatively expeditious process. The availability of high-throughput datasets has cultivated new strategies for drug development and can provide the foundation towards effective therapy options. Molecular modeling methods using structure-based or computer-aided virtual screening can potentially be employed as research guides to identify novel antiviral agents. This review focuses on in-silico modeling of the potential therapeutic candidates against SARS CoVs, in addition to strategies for vaccine design. Here, we particularly focus on the recently published SARS CoV main protease (Mpro) active site, the RNA-dependent RNA polymerase (RdRp) of SARS CoV2, and the spike S-protein as potential targets for vaccine development. This review can offer future perspectives for further research and the development of COVID-19 therapies via the design of new drug candidates and multi-epitopic vaccines and through the repurposing of either approved drugs or drugs under clinical trial.

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