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

Molecules ◽  
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.

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

Biology ◽  
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.

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

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.

scholarly journals Molecular Dynamics Simulation of Barnase: Contribution of Noncovalent Intramolecular Interaction to Thermostability

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Zhiguo Chen ◽  
Yi Fu ◽  
Wenbo Xu ◽  
Ming Li
Keyword(s):  
Molecular Dynamics ◽  
Thermal Stability ◽  
Molecular Dynamics Simulation ◽  
Root Mean Square ◽  
Clinical Medicine ◽  
Intramolecular Interaction ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Mean Square ◽  
Thermal Stability Of

Bacillus amyloliquefaciensribonuclease Barnase (RNase Ba) is a 12 kD (kilodalton) small extracellular ribonuclease. It has broad application prospects in agriculture, clinical medicine, pharmaceutical, and so forth. In this work, the thermal stability of Barnase has been studied using molecular dynamics simulation at different temperatures. The present study focuses on the contribution of noncovalent intramolecular interaction to protein stability and how they affect the thermal stability of the enzyme. Profiles of root mean square deviation and root mean square fluctuation identify thermostable and thermosensitive regions of Barnase. Analyses of trajectories in terms of secondary structure content, intramolecular hydrogen bonds and salt bridge interactions indicate distinct differences in different temperature simulations. In the simulations, Four three-member salt bridge networks (Asp8-Arg110-Asp12, Arg83-Asp75-Arg87, Lys66-Asp93-Arg69, and Asp54-Lys27-Glu73) have been identified as critical salt bridges for thermostability which are maintained stably at higher temperature enhancing stability of three hydrophobic cores. The study may help enlighten our knowledge of protein structural properties, noncovalent interactions which can stabilize secondary peptide structures or promote folding, and also help understand their actions better. Such an understanding is required for designing efficient enzymes with characteristics for particular applications at desired working temperatures.

scholarly journals Use of multiple picosecond high-mass molecular dynamics simulations to predict crystallographic B-factors of folded globular proteins

2016 ◽  
Author(s):  
Yuan-Ping Pang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Root Mean Square ◽  
A Priori ◽  
Model Systems ◽  
Dynamics Simulation ◽  
High Mass ◽  
Mean Square ◽  
Dynamics Simulations

ABSTRACTPredicting crystallographic B-factors of a protein from a conventional molecular dynamics simulation is challenging in part because the B-factors calculated through sampling the atomic positional fluctuations in a picosecond molecular dynamics simulation are unreliable and the sampling of a longer simulation yields overly large root mean square deviations between calculated and experimental B-factors. This article reports improved B-factor prediction achieved by sampling the atomic positional fluctuations in multiple picosecond molecular dynamics simulations that use uniformly increased atomic masses by 100-fold to increase time resolution. Using the third immunoglobulin-binding domain of protein G, bovine pancreatic trypsin inhibitor, ubiquitin, and lysozyme as model systems, the B-factor root mean square deviations (mean ± standard error) of these proteins were 3.1 ± 0.2–9 ± 1 Å2for Cα and 7.3 ± 0.9–9.6 ± 0.2 Å2for Cγ, when the sampling was done, for each of these proteins, over 20 distinct, independent, and 50-picosecond high-mass molecular dynamics simulations using AMBER forcefield FF12MC or FF14SB. These results suggest that sampling the atomic positional fluctuations in multiple picosecond high-mass molecular dynamics simulations may be conducive toa prioriprediction of crystallographic B-factors of a folded globular protein.

Binding Free Energy and the structural changes determination in hGH protein with different concentrations of copper ions (A molecular dynamics simulation study)

2016 ◽  
Vol 15 (05) ◽  
pp. 1650045 ◽  
Author(s):  
Elham Tazikeh-Lemeski
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Surface Area ◽  
Structural Changes ◽  
Copper Ions ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area

In this study, we estimated the optimum concentration of copper ions that are effective in the stability and the structural changes of human growth hormone (hGH) protein in the combination of different concentrations of these ions at the molecular level using molecular dynamics simulation by Gromacs 4.6.5 software. Moreover, to estimate the binding affinity of copper ions to hGH protein, binding free energies is calculated by the molecular mechanics Poisson–Boltzmann Surface Area (MM-PBSA). The analysis of molecular dynamics (MD) trajectories as dictionary of the secondary structure of protein (DSSP), solvent accessible surface area (SASA) and binding free energy calculations show that hGH protein structure is more stabilized by increasing a limited concentration of copper ions. These findings align with our previous experimental studies.

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

Molecules ◽  
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.

scholarly journals Molecular Dynamics Study of Insulin Mutants

2021 ◽  
Keyword(s):  
Molecular Dynamics ◽  
Protein Structure ◽  
Secondary Structure ◽  
Root Mean Square ◽  
Human Insulin ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Mean Square ◽  
Wild Type ◽  
Secondary Structure Content

Human insulin, a small protein hormone consisting of A-chain (21 residues) and B-chain (30 residues) linked by three disulfide bonds, is crucial for controlling the hyperglycemia in type I diabetes. In the present work molecular dynamics simulation (MD) with human insulin and its mutants was used to assess the influence of 10 point mutations (HisA8, ValA10, AspB10, GlnB17, AlaB17, GlnB18, AspB25, ThrB26, GluB27, AspB28), 6 double mutations (GluA13+GluB10, SerA13+GluB27, GluB1+GluB27, SerB2+AspB10, AspB9+GluB27, GluB16+GluB27) and one triple mutation (GluA15+AspA18+AspB3) in the protein sequence on the structure and dynamics of human insulin. A series of thermal unfolding MD simulations with wild type (WT) human insulin and its mutants was performed at 400 K with GROMACS software (version 5.1) using the CHARMM36m force field. The MD results have been analyzed in terms of the parameters characterizing both the global and local protein structure, such as the backbone root mean-square deviation, gyration radius, solvent accessible surface area, the root mean-square fluctuations and the secondary structure content. The MD simulation data showed that depending on time evolution of integral characteristics, the examined mutants can be tentatively divided into three groups: 1) the mutants HisA8, ValA10, AlaB17, AspB25, ThrB26, GluB27, GluA13+GluB10, GluB1+GluB27 and GluB16+GluB27, which exert stabilizing effect on the protein structure in comparison with wild type insulin; 2) the mutants GlnB17, AspB10, SerB2+AspB10 and GluA15+AspA18+AspB3 that did not significantly affect the dynamical properties of human insulin with a minimal stabilizing impact; 3) the mutants AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18, destabilizing the protein structure. Analysis of the secondary structure content provided evidence for the influence of AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18 on the insulin unfolding. Our MD results indicate that the replacement of superficial nonpolar residues in the insulin structure by hydrophilic ones gives rise to the increase in protein stability in comparison with the wild type protein.

MOLECULAR DYNAMICS SIMULATION OF POPC AND POPE LIPID MEMBRANE BILAYERS ENFORCED BY AN INTERCALATED SINGLE-WALL CARBON NANOTUBE

NANO ◽  
2011 ◽  
Vol 06 (01) ◽  
pp. 19-29 ◽  
Author(s):  
SERGEY SHITYAKOV ◽  
THOMAS DANDEKAR
Keyword(s):  
Molecular Dynamics ◽  
Carbon Nanotube ◽  
Molecular Dynamics Simulation ◽  
Root Mean Square ◽  
Lipid Membrane ◽  
Dynamics Simulation ◽  
Mean Square ◽  
Single Wall Carbon Nanotube ◽  
Single Wall Carbon ◽  
Membrane Bilayers

Using classical all-atom molecular dynamics simulation, we investigated the molecular dynamics of palmitoyloleoylphosphatidylcholine and palmitoyloleoylphosphatidylethanolamine membrane bilayers enforced by a single-wall carbon nanotube. We postulated that an insertion of a single-wall carbon nanotube in the center of lipid membrane "strengthens" ambient lipids and prevents the whole system from further destabilization by high temperatures. We implemented root mean square deviation and root mean square fluctuation analyses of simulated structures from their initial states in order to emphasize the molecular dynamics behavior of these structures during 1000 ps simulation time at different temperatures. The data suggest that an intercalated carbon nanotube restrains the conformational freedom of adjacent lipids and hence has an impact on the membrane stabilization dynamics. On the other hand, different lipid membranes may have dissimilarities due to the differing abilities to create a bridge formation between the adherent lipid molecules. The results derived from this work may be of importance in developing stable nanosystems for construction of novel biomaterials and delivery of various biomolecules in the fields of biosensors, biomaterials, and biophysics.

scholarly journals Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

2016 ◽  
Vol 14 (1) ◽  
pp. 188-196 ◽  
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.

scholarly journals Screening of druggable conformers of α-synuclein using molecular dynamics simulation

2020 ◽  
Vol 10 (3) ◽  
pp. 5338-5347
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Secondary Structure ◽  
Surface Area ◽  
Accessible Surface Area ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Binding Pockets ◽  
Accessible Surface ◽  
Solvent Accessible Surface

Intrinsically disordered proteins (IDPs) are becoming an engaging prospect for therapeutic intervention by small drug-like molecules. IDPs structural binding pockets and their flexibility exist as a challenging target for standard druggable approaches. Hence, in this study, we have performed and identified the most probable druggable conformers from molecular dynamics simulation on α-synuclein based on the structural parameters: radius of gyration (Rg), solvent accessible surface area (SASA) and the standard secondary structure content. We found the conformers showing lower solvent accessible surface area and higher secondary structure content of α-helical are defined to be suitable binding pockets for druggability.

Sign in / Sign up

Export Citation Format

Share Document