Binding and inhibitory effect of ravidasvir on 3CLpro of SARS-CoV‐2: a molecular docking, molecular dynamics and MM/PBSA approach

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

Download Full-text

Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies

BioMed Research International ◽

10.1155/2016/4182595 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Ganggang Luo ◽

Fang Lu ◽

Liansheng Qiao ◽

Xi Chen ◽

Gongyu Li ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Inhibitory Effect ◽

Pharmacophore Modeling ◽

Chinese Herbs ◽

Dynamics Simulation ◽

Aldosterone Synthase ◽

Docking Score ◽

Novel Approach ◽

Key Enzyme

Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS) and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment.

Download Full-text

Elucidating the Inhibitory Effect of Resveratrol and Its Structural Analogs on Selected Nucleotide-Related Enzymes

Biomolecules ◽

10.3390/biom10091223 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1223

Author(s):

Yifei Wu ◽

Tze-chen Hsieh ◽

Joseph M. Wu ◽

Xiaoxiao Wang ◽

Joshua S. Christopher ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Ribonucleotide Reductase ◽

Md Simulation ◽

Dna Polymerases ◽

Inhibitory Effect ◽

Inhibitory Effects ◽

Inhibitory Mechanisms ◽

Chain Polymerization ◽

Hiv 1

Resveratrol, the most widely studied natural phytochemical, has been shown to interact with different target proteins. Previous studies show that resveratrol binds and inhibits DNA polymerases and some other enzymes; however, the binding and functioning mechanisms remain unknown. The elucidated knowledge of inhibitory mechanisms of resveratrol will assist us in new drug discovery. We utilized molecular docking and molecular dynamics (MD) simulation to reveal how resveratrol and structurally similar compounds bind to various nucleotide-dependent enzymes, specifically, DNA polymerases, HIV-1 reverse transcriptase, and ribonucleotide reductase. The results show that resveratrol and its analogs exert their inhibitory effects by competing with the substrate dNTPs in these enzymes and blocking elongation of chain polymerization. In addition, the results imply that resveratrol binds to a variety of other ATP-/NTP-binding proteins.

Download Full-text

Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Molecules ◽

10.3390/molecules26247458 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7458

Author(s):

Amin Osman Elzupir

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Mechanics ◽

Surface Area ◽

Active Sites ◽

Inhibitory Effect ◽

Binding Energies ◽

Poisson Boltzmann ◽

The Stability ◽

Dynamics Simulations

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics–Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics–generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from −4.6 ± 0.14 to −7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of −25.53 and −7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.

Download Full-text

Molecular Docking and Molecular Dynamics Simulation Based Approach to Explore the Dual Inhibitor Against HIV-1 Reverse Transcriptase and Integrase

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207320666170615104703 ◽

2017 ◽

Vol 20 (8) ◽

Cited By ~ 11

Author(s):

Subhash Chander ◽

Rajan Kumar Pandey ◽

Ashok Penta ◽

Bhanwar Singh Choudhary ◽

Manish Sharma ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Reverse Transcriptase ◽

Dynamics Simulation ◽

Dual Inhibitor ◽

Simulation Based ◽

Hiv 1

Download Full-text

Design of potential IKK-β inhibitors using molecular docking and molecular dynamics techniques for their anti-cancer potential

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200102121505 ◽

2020 ◽

Vol 16 ◽

Author(s):

Salam Pradeep Singh ◽

Iftikar Hussain ◽

Bolin Kumar Konwar ◽

Ramesh Chandra Deka ◽

Chingakham Brajakishor Singh

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Md Simulation ◽

Inflammatory Diseases ◽

Binding Free Energy ◽

Anti Cancer ◽

Dietary Phytochemicals ◽

Toxicity Analysis ◽

The Stability ◽

Stable Trajectory

Aim and Objective: To evaluate a set of seventy phytochemicals for their potential ability to bind the inhibitor of nuclear factor kappaB kinase beta (IKK-β) which is a prime target for cancer and inflammatory diseases. Materials and Methods: Seventy phytochemicals were screened against IKK-β enzyme using DFT-based molecular docking technique and the top docking hits were carried forward for molecular dynamics (MD) simulation protocols. The adme-toxicity analysis was also carried out for the top docking hits. Results: Sesamin, matairesinol and resveratrol were found to be the top docking hits with a total score of -413 kJ/mol, -398.11 kJ/mol and 266.73 kJ/mol respectively. Glu100 and Gly102 were found to be the most common interacting residues. The result from MD simulation observed a stable trajectory with a binding free energy of -107.62 kJ/mol for matairesinol, -120.37 kJ/mol for sesamin and -40.56 kJ/mol for resveratrol. The DFT calculation revealed the stability of the compounds. The ADME-Toxicity prediction observed that these compounds fall within the permissible area of Boiled-Egg and it does not violate any rule for pharmacological criteria, drug-likeness etc. Conclusion: The study interprets that dietary phytochemicals are potent inhibitors of IKK-β enzyme with favourable binding affinity and less toxic effects. In fact, there is a gradual rise in the use of plant-derived molecules because of its lesser side effects compared to chemotherapy. The study has also provided an insight by which the phytochemicals inhibited the IKK-β enzyme. The investigation would also provide in understanding the inhibitory mode of certain dietary phytochemicals in treating cancer.

Download Full-text

Molecular Docking Study for Analyzing the Inhibitory Effect of Anti-inflammatory Plant Compound Against Tumour Necrosis Factor (TNF-α)

Current Drug Therapy ◽

10.2174/1574885513666180503145352 ◽

2019 ◽

Vol 14 (1) ◽

pp. 85-90

Author(s):

Sagarika Biswas

Keyword(s):

Molecular Docking ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Docking Study ◽

Developed Countries ◽

Inhibitory Effect ◽

Molecular Docking Study ◽

Drug Designing ◽

Anti Inflammatory ◽

Necrosis Factor

Background: Rheumatoid Arthritis (RA) is an autoimmune disorder of symmetric synovial joints which is characterized by the chronic inflammation with 0.5-1% prevalence in developed countries. Presence of persistent inflammation is attributed to the major contribution of key inflammatory cytokine and tumour necrosis factor- alpha (TNF- α). Recent drug designing studies are developing TNF-α blockers to provide relief from the symptoms of the disease such as pain and inflammation. Available blockers are showing certain limitations such as it may enhance the rate of tuberculosis (TB) occurrence, lymphoma risk, cost issues and certain infections are major concern. Discussed limitations implicated a need of development of some alternative drugs which exhibit fewer side effects with low cost. Therefore, we have identified anti-inflammatory compounds in an underutilized fruit of Baccaurea sapida (B.sapida) in our previous studies. Among them quercetin have been identified as the most potent lead compound for drug designing studies of RA. Methods: In the present article, characterization of quercetin has been carried out to check its drug likeliness and molecular docking study has been carried out between TNF- α and quercetin by using AutoDock 4.2.1 software. Further, inhibitory effect of B. sapida fruit extract on RA plasma has been analysed through immunological assay ELISA. Results: Our in-silico analysis indicated that quercetin showed non carcinogenic reaction in animal model and it may also cross the membrane barrier easily. We have studied the ten different binding poses and best binding pose of TNF-α and quercetin showed -6.3 kcal/mol minimum binding energy and 23.94 µM inhibitory constant. In addition to this, ELISA indicated 2.2 down regulated expression of TNF-α in RA compared to control. Conclusion: This study may further be utilized for the drug designing studies to reduce TNF-α mediated inflammation in near future. This attempt may also enhance the utilization of this plant worldwide.

Download Full-text