Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of −8.3, −8.6, and −8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

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Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors

Biology ◽

10.3390/biology10070589 ◽

2021 ◽

Vol 10 (7) ◽

pp. 589

Author(s):

Shafi Mahmud ◽

Suvro Biswas ◽

Gobindo Kumar Paul ◽

Mohasana Akter Mita ◽

Maria Meha Promi ◽

...

Keyword(s):

Root Mean Square ◽

Active Sites ◽

Treatment Options ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Drug Candidates ◽

Main Protease ◽

Antibacterial And Antifungal

Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein–compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.

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Efficacy of Phytochemicals Derived from Avicennia officinalis for the Management of COVID-19: A Combined In Silico and Biochemical Study

Molecules ◽

10.3390/molecules26082210 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2210

Author(s):

Shafi Mahmud ◽

Gobindo Kumar Paul ◽

Mirola Afroze ◽

Shirmin Islam ◽

Swagota Briti Ray Gupt ◽

...

Keyword(s):

Root Mean Square ◽

Antioxidant Activities ◽

Binding Free Energy ◽

Healthcare Management ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Main Protease ◽

Avicennia Officinalis

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

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Reappraisal of Trifluperidol against NSP-3 protein: Potential therapeutic for COVID-19

10.21203/rs.3.rs-52706/v1 ◽

2020 ◽

Author(s):

Ajita Pandey

Keyword(s):

Root Mean Square ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Scoring Functions ◽

Mean Square ◽

Structural Protein ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Novel coronavirus disease 2019 (COVID-19) is a highly infectious disease that is caused by the recently discovered severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Because there are no specific vaccines or drugs for SARS-CoV-2, drug repurposing may be a promising approach. SARS-CoV-2 has a positive-sense RNA genome that encodes non-structural proteins (Nsps), which are essential for viral replication in the host cell. Non-structural protein 3 (Nsp3) is a multidomain protein and is the largest protein of the replicase complex. Nsp3 contains an ADP-ribose phosphatase (ADRP) domain, also called the macrodomain, which interferes with the host immune response. In the present study, we used computational regression methods to target the ADRP domain of Nsp3, using FDA-approved drugs. We virtually screened 2,892 FDA-approved drugs, using a combination of molecular docking and scoring functions. Saquinavir and trifluperidol were identified as potential leads and were further investigated using molecular dynamics simulation (MDS) to predict the stability and behavior of the ADRP-drug complexes. Analysis of root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and number of hydrogen bonds showed that the ADRP-trifluperidol complex is more stable than the ADRP-saquinavir complex. The screening and the MDS results suggest that trifluperidol is a novel inhibitor of the ADRP domain of Nsp3. Trifluperidol could, therefore, potentially be used to help control the spread of COVID-19, either alone or in combination with antiviral agents. Further in-vitro and in-vivo experiments are necessary to confirm our in silico results.

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Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

Open Chemistry ◽

10.1515/chem-2016-0021 ◽

2016 ◽

Vol 14 (1) ◽

pp. 188-196 ◽

Cited By ~ 1

Author(s):

Syed Lal Badshah ◽

Abdul Naeem Khan ◽

Yahia Nasser Mabkhot

Keyword(s):

Molecular Dynamics ◽

Secondary Structure ◽

Cholera Toxin ◽

Root Mean Square ◽

Host Cells ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Toxin A

AbstractA molecular dynamics (MD) simulation study of the enzymatic portion of cholera toxin; cholera toxin A-1 polypeptide (CTA1) was performed at 283, 310 and 323 K. From total energy analysis it was observed that this toxin is stable thermodynamically and these outcomes were likewise confirmed by root mean square deviations (RMSD) investigations. The Cα root mean square fluctuation (RMSF) examinations revealed that there are a number of residues inside CTA1, which can be used as target for designing and synthesizing inhibitory drugs, in order to inactivate cholera toxin inside the human body. The fluctuations in the radius of gyration and hydrogen bonding in CTA1 proved that protein unfolding and refolding were normal routine phenomena in its structure at all temperatures. Solvent accessible surface area study identified the hydrophilic nature of the CTA1, and due to this property it can be a potential biological weapon. The structural identification (STRIDE) algorithm for proteins was successfully used to determine the partially disordered secondary structure of CTA1. On account of this partially disordered secondary structure, it can easily deceive the proteolytic enzymes of the endoplasmic reticulum of host cells.

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Effects of the Temperature and the pH on the Main Protease of SARS-CoV-2: A Molecular Dynamics Simulation Study

Biointerface Research in Applied Chemistry ◽

10.33263/briac126.72397248 ◽

2021 ◽

Vol 12 (6) ◽

pp. 7239-7248

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Root Mean Square ◽

Dynamics Simulation ◽

Effect Of Temperature ◽

Water Molecules ◽

Mean Square ◽

Main Protease ◽

Decreasing Ph ◽

Increasing Temperature

The novel coronavirus, recognized as COVID-19, is the cause of an infection outbreak in December 2019. The effect of temperature and pH changes on the main protease of SARS-CoV-2 were investigated using all-atom molecular dynamics simulation. The obtained results from the root mean square deviation (RMSD) and root mean square fluctuations (RMSF) analyses showed that at a constant temperature of 25℃ and pH=5, the conformational change of the main protease is more significant than that of pH=6 and 7. Also, by increasing temperature from 25℃ to 55℃ at constant pH=7, a remarkable change in protein structure was observed. The radial probability of water molecules around the main protease was decreased by increasing temperature and decreasing pH. The weakening of the binding energy between the main protease and water molecules due to the increasing temperature and decreasing pH has reduced the number of hydrogen bonds between the main protease and water molecules. Finding conditions that alter the conformation of the main protease could be fundamental because this change could affect the virus’s functionality and its ability to impose illness.

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Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

Molecules ◽

10.3390/molecules25204829 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4829

Author(s):

Sajjad Haider ◽

Assem Barakat ◽

Zaheer Ul-Haq

Keyword(s):

Virtual Screening ◽

Molecular Dynamic ◽

Root Mean Square ◽

Cancer Metastasis ◽

Pharmacophore Model ◽

Binding Mode ◽

Dynamics Simulation ◽

Radius Of Gyration ◽

Mean Square ◽

Dynamic Simulations

CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.

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Phytochemicals from Leucas zeylanica Targeting Main Protease of SARS-CoV-2: Chemical Profiles, Molecular Docking, and Molecular Dynamics Simulations

Biology ◽

10.3390/biology10080789 ◽

2021 ◽

Vol 10 (8) ◽

pp. 789

Author(s):

Mycal Dutta ◽

Abu Montakim Tareq ◽

Ahmed Rakib ◽

Shafi Mahmud ◽

Saad Ahmed Sami ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Surface Area ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Gas Chromatography Mass Spectrometry ◽

Radius Of Gyration ◽

Hydrogen Bond Formation ◽

Main Protease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a contemporary coronavirus, has impacted global economic activity and has a high transmission rate. As a result of the virus’s severe medical effects, developing effective vaccinations is vital. Plant-derived metabolites have been discovered as potential SARS-CoV-2 inhibitors. The SARS-CoV-2 main protease (Mpro) is a target for therapeutic research because of its highly conserved protein sequence. Gas chromatography–mass spectrometry (GC-MS) and molecular docking were used to screen 34 compounds identified from Leucas zeylanica for potential inhibitory activity against the SARS-CoV-2 Mpro. In addition, prime molecular mechanics–generalized Born surface area (MM-GBSA) was used to screen the compound dataset using a molecular dynamics simulation. From molecular docking analysis, 26 compounds were capable of interaction with the SARS-CoV-2 Mpro, while three compounds, namely 11-oxa-dispiro[4.0.4.1]undecan-1-ol (−5.755 kcal/mol), azetidin-2-one 3,3-dimethyl-4-(1-aminoethyl) (−5.39 kcal/mol), and lorazepam, 2TMS derivative (−5.246 kcal/mol), exhibited the highest docking scores. These three ligands were assessed by MM-GBSA, which revealed that they bind with the necessary Mpro amino acids in the catalytic groove to cause protein inhibition, including Ser144, Cys145, and His41. The molecular dynamics simulation confirmed the complex rigidity and stability of the docked ligand–Mpro complexes based on the analysis of mean radical variations, root-mean-square fluctuations, solvent-accessible surface area, radius of gyration, and hydrogen bond formation. The study of the postmolecular dynamics confirmation also confirmed that lorazepam, 11-oxa-dispiro[4.0.4.1]undecan-1-ol, and azetidin-2-one-3, 3-dimethyl-4-(1-aminoethyl) interact with similar Mpro binding pockets. The results of our computerized drug design approach may assist in the fight against SARS-CoV-2.

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Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development

Molecules ◽

10.3390/molecules26061767 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1767

Author(s):

Mohamed E. Abouelela ◽

Hamdy K. Assaf ◽

Reda A. Abdelhamid ◽

Ehab S. Elkhyat ◽

Ahmed M. Sayed ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Drug Development ◽

Root Mean Square ◽

In Silico ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculation ◽

Mean Square ◽

Main Protease

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.

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Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

Molecules ◽

10.3390/molecules26216538 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6538

Author(s):

Md. Mominur Rahman ◽

Md. Junaid ◽

S. M. Zahid Hosen ◽

Mohammad Mostafa ◽

Lei Liu ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Surface Area ◽

Root Mean Square ◽

Selective Inhibition ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Mean Square ◽

Cox 1

Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.

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Investigating the role of N-terminal domain in phosphodiesterase 4B-inhibition by molecular dynamics simulation

10.1101/2020.05.12.090993 ◽

2020 ◽

Author(s):

Vidushi Sharma ◽

Sharad Wakode

Keyword(s):

Ligand Binding ◽

Root Mean Square ◽

Active Site ◽

Binding Pocket ◽

Dynamics Simulation ◽

Radius Of Gyration ◽

Mean Square ◽

Sequence Identity ◽

Terminal Domain ◽

Phosphodiesterase 4B

AbstractPhosphodiesterase 4B (PDE4B) is a potential therapeutic target for the inflammatory respiratory diseases such as congestive obstructive pulmonary disease (COPD) and asthma. The sequence identity of ∼88% with its isoform PDE4D is the key barrier in developing selective PDE4B inhibitors which may help to overcome associated side effects. Despite high sequence identity, both isoforms differ in few residues present in N-terminal (UCR2) and C-terminal (CR3) involved in catalytic site formation. Previously, we designed and tested specific PDE4B inhibitors considering N-terminal residues as a part of the catalytic cavity. In continuation, current work thoroughly presents an MD simulation-based analysis of N-terminal residues and their role in ligand binding. The various parameters viz. root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), principal component analysis (PCA), dynamical cross-correlation matrix (DCCM) analysis, secondary structure analysis, and residue interaction mapping were investigated to establish rational. Results showed that UCR2 reduced RMSF values for the metal binding pocket (31.5±11 to 13.12±6 Å2) and the substrate-binding pocket (38.8±32 to 17.3±11 Å2). UCR2 enhanced anti-correlated motion at the active site region that led to the improved ligand-binding affinity of PDE4B from −24.57±3 to −35.54±2 kcal/mol. Further, the atomic-level analysis indicated that T-pi and π-π interactions between inhibitors and residues are vital forces that regulate inhibitor association to PDE4B with high affinity. In conclusion, UCR2, the N-terminal domain, embraces the dynamics of PDE4B active site and stabilizes PDE4B inhibitor interactions. Therefore the N-terminal domain needs to be included by designing next-generation, selective PDE4B-inhibitors as potential anti-inflammatory drugs.

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