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 Computer-aided approaches reveal trihydroxychroman and pyrazolone derivatives as potential inhibitors of SARS-CoV-2 virus main protease

2021 ◽  
Vol 71 (3) ◽  
pp. 325-333
Author(s):  
Noor Atatreh ◽  
Shaima Hasan ◽  
Bassam R. Ali ◽  
Mohammad A. Ghattas
Keyword(s):  
Protein Complexes ◽  
Binding Energies ◽  
World Health ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
Protease Enzyme ◽  
Main Protease ◽  
Pyrazolone Derivatives ◽  
Starting Point ◽  
Potential Inhibitors

AbstractCOVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The aim of this study is to target the SARS-CoV-2 virus main protease (Mpro) via structure-based virtual screening. Consequently, > 580,000 ligands were processed via several filtration and docking steps, then the top 21 compounds were analysed extensively via MM-GBSA scoring and molecular dynamic simulations. Interestingly, the top compounds showed favorable binding energies and binding patterns to the protease enzyme, forming interactions with several key residues. Trihydroxychroman and pyrazolone derivatives, SN02 and SN18 ligands, exhibited very promising binding modes along with the best MM-GBSA scoring of –40.9 and –41.2 kcal mol−1, resp. MD simulations of 300 ns for the ligand-protein complexes of SN02 and SN18 affirmed the previously attained results of the potential inhibition activity of these two ligands. These potential inhibitors can be the starting point for further studies to pave way for the discovery of new antiviral drugs for SARS-CoV-2.

scholarly journals Natural Polyphenols Inhibit the Dimerization of the SARS-CoV-2 Main Protease: The Case of Fortunellin and Its Structural Analogs

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6068
Author(s):  
Athanasios A. Panagiotopoulos ◽  
Ioannis Karakasiliotis ◽  
Danai-Maria Kotzampasi ◽  
Marios Dimitriou ◽  
George Sourvinos ◽  
...  
Keyword(s):  
Natural Products ◽  
Dietary Supplements ◽  
Plaque Formation ◽  
Drug Candidates ◽  
Natural Polyphenols ◽  
Main Protease ◽  
Main Target ◽  
Viral Plaque ◽  
Potential Inhibitors

3CL-Pro is the SARS-CoV-2 main protease (MPro). It acts as a homodimer to cleave the large polyprotein 1ab transcript into proteins that are necessary for viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and a main target of therapeutics. A number of drug candidates have been reported, including natural products. Here, we employ elaborate computational methods to explore the dimerization of the 3CL-Pro protein, and we formulate a computational context to identify potential inhibitors of this process. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, and its structural analogs are potent inhibitors of 3CL-Pro dimerization, inhibiting viral plaque formation in vitro. We thus propose a novel basis for the search of pharmaceuticals as well as dietary supplements in the fight against SARS-CoV-2 and COVID-19.

scholarly journals An in-silico evaluation of COVID-19 main protease with clinically approved drugs

2020 ◽  
Author(s):  
TACHOUA Wafa ◽  
KABRINE Mohamed ◽  
Mamona Mushtaq ◽  
Zaheer Ul-Haq
Keyword(s):  
Conformational Dynamics ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Binding Affinities ◽  
Binding Modes ◽  
Wuhan City ◽  
Main Protease ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Binding Substrate

<p></p><p>A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease M<sup>pro</sup> with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against M<sup>pro </sup>crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CL<sup>pro</sup>) of SARS-CoV-2. </p><br><p></p>

scholarly journals An in-silico evaluation of COVID-19 main protease with clinically approved drugs

2020 ◽  
Author(s):  
TACHOUA Wafa ◽  
KABRINE Mohamed ◽  
Mamona Mushtaq ◽  
Zaheer Ul-Haq
Keyword(s):  
Conformational Dynamics ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Binding Affinities ◽  
Binding Modes ◽  
Wuhan City ◽  
Main Protease ◽  
Approved Drugs ◽  
Potential Inhibitors ◽  
Binding Substrate

<p></p><p>A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease M<sup>pro</sup> with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against M<sup>pro </sup>crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CL<sup>pro</sup>) of SARS-CoV-2. </p><br><p></p>

scholarly journals Consensus Virtual Screening of Dark Chemical Matter and Food Chemicals Uncover Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Marisa G. Santibáñez-Morán ◽  
Edgar López-López ◽  
Fernando D. Prieto-Martínez ◽  
Norberto Sánchez-Cruz ◽  
Jose L. Medina-Franco
Keyword(s):  
Virtual Screening ◽  
Chemical Space ◽  
Experimental Testing ◽  
Consensus Approach ◽  
Computational Tools ◽  
Drug Candidates ◽  
Main Protease ◽  
Selection For ◽  
Potential Inhibitors ◽  
Chemical Matter

The COVID-19 pandemic caused by SARS-CoV-2 has claimed more than 380,000 lives Worldwide and more than 6.5 million people are infected. Unfortunately, there is no drug or vaccine for the treatment of COVID-19. The increasing information available of key molecular targets of SARS-CoV-2 and active compounds against related coronavirus facilitates computational tools to rapidly suggest drug candidates for the treatment of COVID-19. As part of a global effort to fight the COVID-19 pandemic, herein we report a consensus virtual screening of large collections of food chemicals and compounds classified as Dark Chemical Matter. The rationale is to complement global efforts and explore regions of the chemical space currently underexplored. The consensus approach included combining similarity searching with various queries and fingerprints, molecular docking with two docking programs, and ADMETox profiling. We propose three compounds commercially available that were sent to experimental testing. We disclose the full list of virtual screening hits that can be subject to additional selection for acquisition or synthesis and experimental testing. This manuscript will be updated when the experimental testing of the selected compounds becomes available.

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

scholarly journals Prioritization of Potential Drugs Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yanjin Li ◽  
Yu Zhang ◽  
Yikai Han ◽  
Tengfei Zhang ◽  
Ranran Du
Keyword(s):  
Large Scale ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Neural Activities ◽  
Main Protease ◽  
Global Threat ◽  
Potential Inhibitors ◽  
Molecular Patterns ◽  
Effective Drugs ◽  
Large Scale Screening

<p> Since its outbreak in 2019, the acute respiratory syndrome caused by SARS-Cov-2 has become a severe global threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this pandemic disease. Here we employed a computational approach to prioritize potential inhibitors that directly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing the viral RNA-translated polyprotein into functional proteins for viral replication. Based on a large-scale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that may suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known replication inhibitor of hepatitis C virus (HCV), which is recently reported to inhibit SARS-Cov-2 as well. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a novel molecular similarity between this respiratory syndrome and neural activities. Our approach not only provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals intriguing molecular patterns that are worth future explorations.</p>

scholarly journals Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

scholarly journals Discovery of Potent Covid-19 Main Protease Inhibitors Using Machine Learning Based Virtual Screening Strategy

2020 ◽  
Author(s):  
Muthu Kumar T ◽  
Rohini K ◽  
Nivya James ◽  
Shanthi V ◽  
Ramanathan Karuppasamy
Keyword(s):  
Machine Learning ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Screening Strategy ◽  
Antiviral Therapies ◽  
Drug Molecules ◽  
Main Protease ◽  
Antiviral Activities ◽  
Imminent Threat ◽  
Potential Inhibitors

<p>The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the great role of main protease of Covid-19 for virus replication, we performed drug repurposing study using recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR respectively were developed using available small molecule inhibitors and utilized in the screening of DrugBank repository. Further, hierarchical docking protocol was implemented with the support of Glide algorithm. The resultant compounds were then examined for its binding free energy against main protease of Covid-19 by means of Prime-MM/GBSA algorithm. Most importantly, the resultant compounds antiviral activities were further predicted by machine learning-based model generated by AutoQSAR algorithm. Finally, the hit molecules were examined for its drug likeness and its toxicity parameters through QikProp algorithm. Overall, the present analysis yielded four potential inhibitors (DB07800, DB08573, DB03744 and DB02986) that are predicted to bind with main protease of Covid-19 better than currently used drug molecules such as N3 (co-crystallized native ligand), Lopinavir and Ritonavir. </p>

scholarly journals In silico Screening of Natural Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike RBD: Targets for COVID-19

2021 ◽  
Vol 7 ◽  
Author(s):  
Divya M. Teli ◽  
Mamta B. Shah ◽  
Mahesh T. Chhabria
Keyword(s):  
Binding Free Energy ◽  
Treatment Options ◽  
Natural Compounds ◽  
Pharmacokinetic Parameters ◽  
Main Protease ◽  
Glide Docking ◽  
Docking Approach ◽  
Covalent Docking ◽  
Dual Inhibitors ◽  
Potential Inhibitors

Historically, plants have been sought after as bio-factories for the production of diverse chemical compounds that offer a multitude of possibilities to cure diseases. To combat the current pandemic coronavirus disease 2019 (COVID-19), plant-based natural compounds are explored for their potential to inhibit the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of COVID-19. The present study is aimed at the investigation of antiviral action of several groups of phytoconstituents against SARS-CoV-2 using a molecular docking approach to inhibit Main Protease (Mpro) (PDB code: 6LU7) and spike (S) glycoprotein receptor binding domain (RBD) to ACE2 (PDB code: 6M0J) of SARS-CoV-2. For binding affinity evaluation, the docking scores were calculated using the Extra Precision (XP) protocol of the Glide docking module of Maestro. CovDock was also used to investigate covalent docking. The OPLS3e force field was used in simulations. The docking score was calculated by preferring the conformation of the ligand that has the lowest binding free energy (best pose). The results are indicative of better potential of solanine, acetoside, and rutin, as Mpro and spike glycoprotein RBD dual inhibitors. Acetoside and curcumin were found to inhibit Mpro covalently. Curcumin also possessed all the physicochemical and pharmacokinetic parameters in the range. Thus, phytochemicals like solanine, acetoside, rutin, and curcumin hold potential to be developed as treatment options against COVID-19.

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