Abstract 712: Anticancer natural compounds as potential inhibitors of novel coronavirus (COVID19) main protease: An in-silico study

Abstract COVID-19 pandemic, a novel coronavirus disease is caused by severe acute respiratory syndrome corona virus, SARS-CoV-2. It was first reported in Wuhan, China and has now expanded to more than 190 countries across the world. Till date, there is no specific medication available to prevent or target SARS CoV-2 infection. Very recently, the crystal structure of COVID- 19 main protease (Mpro) was revealed by Liu et al. (2020). SARS-CoV-2 main protease (Mpro) is a key enzyme that plays a crucial role in viral replication and transcription. Thus, Mpro could be a promising target to inhibit SARS-CoV-2 infection. Natural compounds due to their structural diversity and safety are considered as an excellent source of antiviral drugs. In this study, we selected Herbacetin, Rhoifolin, Pectolinarin, Apigenin, Luteolin, Amentoflavone, Daidzein, Puerarin, Epigallocatechin, Gallocatechin gallate, Resveratrol, Maslinic acid, Piperine and Ganomycin B to target the SARS-CoV-2 main protease (Mpro) using in silico tools. These compounds were examined based on ADME, drug likeness, docking studies, MD simulations using CABS-flex 2.0, and prediction of major toxicity parameters (hepatotoxicity & cytotoxicity) to check the safety aspects of the selected compounds. We also investigated the similarity of these compounds, if any, with FDA approved drugs using Swiss similarity. The docking results were found in the order of Amentoflavone (-9.13 kcal/mol), Ritonavir (-8.52 kcal/mol), Lopinavir (-8.5 kcal/mol), Puerarin (-7.97 kcal/mol), Maslinic acid (-7.97 kcal/mol), Piperine (-7.65 kcal/mol), Gallocatechin gallate (-7.59 kcal/mol), Luteolin (-7.58 kcal/mol), Apigenin (-7.42 kcal/mol), Resveratrol (-7.41 kcal/mol), Herbacetin (-7.4 kcal/mol), Daidzein (-7.32 kcal/mol), Rhoifolin (-6.71 kcal/mol), Ganomycin B (-6.46 kcal/mol), Epigallocatechin (-6.13 kcal/mol), and Pectolinarin (-5.88 kcal/mol). Among these selected natural compounds, Amentoflavone and Puerarin were the two top leads which showed the lowest binding energies. Interestingly, Amentoflavone showed highest binding affinity among all the selected compounds. Our promising findings based on in-silico studies warrants further clinical trial in order to use these compounds as potential inhibitors of SARS-CoV-2 protease.

Download Full-text

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

10.26434/chemrxiv.12111297 ◽

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

The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1st, 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, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, 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 darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2.

Download Full-text

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

10.26434/chemrxiv.12111297.v2 ◽

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

The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1st, 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, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, 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 darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2.

Download Full-text

In silico study of medicinal plants with cyclodextrin inclusion complex as the potential inhibitors against SARS-CoV-2 main protease (Mpro) and spike (S) receptor

Informatics in Medicine Unlocked ◽

10.1016/j.imu.2021.100645 ◽

2021 ◽

pp. 100645

Author(s):

Doni Dermawan ◽

Bagas Adji Prabowo ◽

Casilda Aulia Rakhmadina

Keyword(s):

Medicinal Plants ◽

Inclusion Complex ◽

In Silico ◽

Cyclodextrin Inclusion ◽

Main Protease ◽

In Silico Study ◽

Cyclodextrin Inclusion Complex ◽

Potential Inhibitors

Download Full-text

Phenolics from the heartwood of Tecoma mollis as potential inhibitors of COVID-19 virus main protease and spike proteins: An In silico study

Pharmacognosy Magazine ◽

10.4103/pm.pm_35_21 ◽

2021 ◽

Vol 17 (6) ◽

pp. 278

Author(s):

WaelMostafa Abdel-Mageed ◽

LamyaH Al-Wahaibi ◽

MdTabish Rehman ◽

MuneeraS M. Al-Saleem ◽

OmerA Basudan ◽

...

Keyword(s):

In Silico ◽

Main Protease ◽

In Silico Study ◽

Potential Inhibitors ◽

Spike Proteins

Download Full-text

In-Silico Drug Repurposing for Targeting SARS-CoV-2 Mpro

10.26434/chemrxiv.12210845 ◽

2020 ◽

Author(s):

Shilpa Sharma ◽

Shashank Deep

Keyword(s):

In Silico ◽

Drug Targets ◽

Md Simulation ◽

Chemical Constituents ◽

Drug Repurposing ◽

Viral Disease ◽

Ayurvedic Drugs ◽

Main Protease ◽

Novel Coronavirus ◽

Potential Inhibitors

COVID-19, caused by novel coronavirus or SARS-CoV-2, is a viral disease which has infected millions worldwide. Considering the urgent need of the drug for fighting against this infectious disease, we performed in-silico drug repurposing. The main protease (Mpro) is one of the best characterized drug targets among coronaviruses, therefore, this was screened for already known drugs, including chemical constituents of Ayurvedic drugs, using docking and MD simulation. The results suggest EGCG, withaferin A and artesunate may act as potential inhibitors of the main protease (Mpro).

Download Full-text

Natural compounds as potential inhibitors of novel coronavirus (COVID-19) main protease: An in silico study

10.21203/rs.3.rs-22839/v2 ◽

2020 ◽

Author(s):

Amaresh Mishra ◽

Yamini Pathak ◽

Gourav Choudhir ◽

Anuj Kumar ◽

Surabhi Kirti Mishra ◽

...

Keyword(s):

Free Energy ◽

In Silico ◽

Molecular Mechanic ◽

Natural Compounds ◽

Free Energy Calculations ◽

Docking Analysis ◽

Energy Calculations ◽

Lipinski’S Rule ◽

Main Protease ◽

Potential Inhibitors

Abstract COVID-19 pandemic has now expanded over 213 nations across the world. To date, there is no specific medication available for SARS CoV-2 infection. The main protease (Mpro) of SARS CoV-2 plays a crucial role in viral replication and transcription and thereby considered as an attractive drug target for the inhibition of COVID-19,. Natural compounds are widely recognised as valuabe source of antiviral drugs due to their structural diversity and safety. In the current study, we have screened twenty natural compounds having antiviral properties to discover the potential inhibitor molecules against Mpro of COVID-19. Systematic molecular docking analysis was conducted using AuroDock 4.2 to determine the binding affinities and interactions between natural compounds and the Mpro. Out of twenty molecules, four natural metabolites namely, amentoflavone, guggulsterone, puerarin, and piperine were found to have strong interaction with Mpro of COVID-19 based on the docking analysis. These selected natural compounds were further validated using combination of molecular dynamic simulations and molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations. During MD simulations, all four natural compounds bound to Mpro on 50ns and MM/G/P/BSA free energy calculations showed that all four shortlisted ligands have stable and favourable energies causing strong binding with binding site of Mpro protein. These four natural compounds have passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property as well as Lipinski’s rule of five. Our promising findings based on in-silico studies warrant further clinical trials in order to use these natural compounds as potential inhibitors of Mpro protein of COVID.

Download Full-text

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

10.26434/chemrxiv.12111297.v1 ◽

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

The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1st, 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, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, 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 darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2.

Download Full-text

In-Silico Drug Repurposing for Targeting SARS-CoV-2 Mpro

10.26434/chemrxiv.12210845.v1 ◽

2020 ◽

Author(s):

Shilpa Sharma ◽

Shashank Deep

Keyword(s):

In Silico ◽

Drug Targets ◽

Md Simulation ◽

Chemical Constituents ◽

Drug Repurposing ◽

Viral Disease ◽

Ayurvedic Drugs ◽

Main Protease ◽

Novel Coronavirus ◽

Potential Inhibitors

COVID-19, caused by novel coronavirus or SARS-CoV-2, is a viral disease which has infected millions worldwide. Considering the urgent need of the drug for fighting against this infectious disease, we performed in-silico drug repurposing. The main protease (Mpro) is one of the best characterized drug targets among coronaviruses, therefore, this was screened for already known drugs, including chemical constituents of Ayurvedic drugs, using docking and MD simulation. The results suggest EGCG, withaferin A and artesunate may act as potential inhibitors of the main protease (Mpro).

Download Full-text