Potential inhibitors for SARS-CoV-2 Mpro from marine compounds

Nguyen Minh Tam; Minh Quan Pham; Huy Truong Nguyen; Nam Dao Hong; Nguyen Khoa Hien; Duong Tuan Quang; Huong Thi Thu Phung; Son Tung Ngo

doi:10.1039/d1ra03852d

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.

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

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.599079 ◽

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

10.21203/rs.3.rs-22839/v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Amaresh Mishra ◽

Yamini Pathak ◽

Vishwas Tripathi

Keyword(s):

In Silico ◽

Structural Diversity ◽

Natural Compounds ◽

Binding Energies ◽

Maslinic Acid ◽

Main Protease ◽

In Silico Studies ◽

Gallocatechin Gallate ◽

Novel Coronavirus ◽

Potential Inhibitors

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.

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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.

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

10.1158/1538-7445.am2021-712 ◽

2021 ◽

Author(s):

Amaresh Mishra ◽

Yamini Pathak ◽

Gourav Choudhir ◽

Anuj Kumar ◽

Surabhi Kirti Mishra ◽

...

Keyword(s):

In Silico ◽

Natural Compounds ◽

Main Protease ◽

In Silico Study ◽

Novel Coronavirus ◽

Potential Inhibitors

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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.

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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.

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Natural Compounds and Drug Discovery: Can Cnidarian Venom Play a Role?

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666190227234834 ◽

2019 ◽

Vol 19 (2) ◽

pp. 114-118

Author(s):

Gian Luigi Mariottini ◽

Irwin Darren Grice

Keyword(s):

Biological Activity ◽

Marine Species ◽

Natural Compounds ◽

Therapeutic Agents ◽

Industrial Applications ◽

Bioactive Molecules ◽

Sea Anemones ◽

Therapeutic Approaches ◽

Ongoing Research ◽

Biological Compounds

Natural compounds extracted from organisms and microorganisms are an important resource for the development of drugs and bioactive molecules. Many such compounds have made valuable contributions in diverse fields such as human health, pharmaceutics and industrial applications. Presently, however, research on investigating natural compounds from marine organisms is scarce. This is somewhat surprising considering that the marine environment makes a major contribution to Earth's ecosystems and consequently possesses a vast storehouse of diverse marine species. Interestingly, of the marine bioactive natural compounds identified to date, many are venoms, coming from Cnidarians (jellyfish, sea anemones, corals). Cnidarians are therefore particularly interesting marine species, producing important biological compounds that warrant further investigation for their development as possible therapeutic agents. From an experimental aspect, this review aims to emphasize and update the current scientific knowledge reported on selected biological activity (antiinflammatory, antimicrobial, antitumoral, anticoagulant, along with several less studied effects) of Cnidarian venoms/extracts, highlighting potential aspects for ongoing research towards their utilization in human therapeutic approaches.

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Hydrazones of 4-(Trifluoromethyl)benzohydrazide as New Inhibitors of Acetyl- and Butyrylcholinesterase

Molecules ◽

10.3390/molecules26040989 ◽

2021 ◽

Vol 26 (4) ◽

pp. 989

Author(s):

Martin Krátký ◽

Katarína Svrčková ◽

Quynh Anh Vu ◽

Šárka Štěpánková ◽

Jarmila Vinšová

Keyword(s):

Biological Activity ◽

Mixed Type ◽

Cholinesterase Inhibitors ◽

Eukaryotic Cell ◽

Structure Activity ◽

Aliphatic Ketones ◽

Ic50 Values ◽

Central Nervous Systems ◽

Dual Inhibition ◽

Potential Inhibitors

Based on the broad spectrum of biological activity of hydrazide–hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman’s spectrophotometric method. The hydrazide–hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8–137.7 µM and 19.1–881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N’-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure–activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide–hydrazone scaffold.

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