scholarly journals In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

2021 ◽  
Author(s):  
Guangya Xu ◽  
Shutao Zhang ◽  
Lulu Zheng ◽  
Zhongjiao Hu ◽  
Lijia Cheng ◽  
...  
Keyword(s):  
Decomposition Analysis ◽  
Md Simulations ◽  
Energy Decomposition Analysis ◽  
Promising Candidate ◽  
Generalized Born ◽  
A2a Receptor ◽  
The Central Nervous System ◽  
A1 Receptor ◽  
In Silico Identification ◽  
Dynamics Simulations

AbstractMost recently, the adenosine is considered as one of the most promising targets for treating pain, with few side effects. It exists in the central nervous system, and plays a key role in nociceptive afferent pathway. It is reported that the A1 receptor (A1R) could inhibit Ca2+ channels to reduce the pain like analgesic mechanism of morphine. And, A2a receptor (A2aR) was reported to enhance the accumulation of AMP (cAMP) and released peptides from sensory neurons, resulting in constitutive activation of pain. Much evidence showed that A1R and A2aR could be served as the interesting targets for the treatment of pain. Herein, virtual screening was utilized to identify the small molecule compounds towards A1R and A2aR, and top six molecules were considered as candidates via amber scores. The molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to further analyze the affinity and binding stability of the six molecules towards A1R and A2aR. Moreover, energy decomposition analysis showed significant residues in A1R and A2aR, including His1383, Phe1276, and Glu1277. It provided basics for discovery of novel agonists and antagonists. Finally, the agonists of A1R (ZINC19943625, ZINC13555217, and ZINC04698406) and inhibitors of A2aR (ZINC19370372, ZINC20176051, and ZINC57263068) were successfully recognized. Taken together, our discovered small molecules may serve as the promising candidate agents for future pain research.

scholarly journals Binding Affinities of Sanggenon Derivatives as PTP1B Inhibitors; Using Molecular Dynamics and Free Energy Calculations

2021 ◽  
Author(s):  
Safak OZHAN KOCAKAYA
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Tyrosine Phosphatase ◽  
Decomposition Analysis ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Free Energy Decomposition ◽  
Poisson Boltzmann ◽  
Ptp1b Inhibitors

Abstract Recently, protein tyrosine phosphatase 1B (PTP1B) inhibitors have become the frontier as possible targeting for anti-cancer and antidiabetic drugs. The contemporary observe represents a pc assisted version to investigate the importance of precise residues within the binding web site of PTP1B with numerous Sanggenon derivatives remoted from nature. Molecular dynamics (MD) simulations were performed to estimate the dynamics of the complexes, and absolute binding unfastened energies have been calculated with exclusive additives, and carried out through the usage of the Molecular Mechanics-Poisson-Boltzmann floor region (MM-PB/SA) and Generalized Born surface vicinity (MM-GB/SA) strategies. The effects show that the expected free energies of the complexes are normally constant with the available experimental statistics. MM/GBSA free energy decomposition analysis shows that the residues Asp29, Arg24, Met258, and , Arg254 in the second active site in PTP1B are crucial for the excessive selectivity of the inhibitors.

scholarly journals Simulating Chalcogen Bonding Using Molecular Mechanics: A Pseudoatom Approach to Model Ebselen.

2020 ◽  
Author(s):  
Thomas Fellowes ◽  
JONATHAN WHITE
Keyword(s):  
Decomposition Analysis ◽  
Md Simulations ◽  
Accurate Method ◽  
Energy Decomposition Analysis ◽  
Selenium Atom ◽  
Biological Macromolecules ◽  
Energy Decomposition ◽  
Amber Force Field ◽  
Sigma Hole ◽  
Positively Charged

The organoselenium compound ebselen has recently been investigated as a treatment for COVID-19, however<br>efforts to model ebselen in silico have been hampered by the lack of a efficient and accurate method to assess<br>its binding to biological macromolecules. We present here a Generalized Amber Force Field modification which<br>incorporates classical parameters for the selenium atom in ebselen, as well as a positively charged pseudoatom to<br>simulate the sigma?-hole, a quantum mechanical phenomenon that dominates the chemistry of ebselen. Our approach<br>is justified using an energy decomposition analysis of a number DFT optimised structures, which shows that the<br>?sigma-hole interaction is primarily electrostatic in origin. Finally, our model is verified by conducting MD simulations<br>on a number of simple complexes, as well the clinically relevant SOD1, which is known to bind to ebselen.

scholarly journals Simulating Chalcogen Bonding Using Molecular Mechanics: A Pseudoatom Approach to Model Ebselen.

2020 ◽  
Author(s):  
Thomas Fellowes ◽  
JONATHAN WHITE
Keyword(s):  
Decomposition Analysis ◽  
Md Simulations ◽  
Accurate Method ◽  
Energy Decomposition Analysis ◽  
Selenium Atom ◽  
Biological Macromolecules ◽  
Energy Decomposition ◽  
Amber Force Field ◽  
Sigma Hole ◽  
Positively Charged

The organoselenium compound ebselen has recently been investigated as a treatment for COVID-19, however<br>efforts to model ebselen in silico have been hampered by the lack of a efficient and accurate method to assess<br>its binding to biological macromolecules. We present here a Generalized Amber Force Field modification which<br>incorporates classical parameters for the selenium atom in ebselen, as well as a positively charged pseudoatom to<br>simulate the sigma?-hole, a quantum mechanical phenomenon that dominates the chemistry of ebselen. Our approach<br>is justified using an energy decomposition analysis of a number DFT optimised structures, which shows that the<br>?sigma-hole interaction is primarily electrostatic in origin. Finally, our model is verified by conducting MD simulations<br>on a number of simple complexes, as well the clinically relevant SOD1, which is known to bind to ebselen.

scholarly journals Identification of 13 Guanidinobenzoyl- or Aminidinobenzoyl-Containing Drugs to Potentially Inhibit TMPRSS2 for COVID-19 Treatment

2021 ◽  
Vol 22 (13) ◽  
pp. 7060
Author(s):  
Xiaoqiang Huang ◽  
Robin Pearce ◽  
Gilbert S. Omenn ◽  
Yang Zhang
Keyword(s):  
Viral Entry ◽  
Catalytic Domain ◽  
Binding Free Energy ◽  
Decomposition Analysis ◽  
Salt Bridge ◽  
Domain Model ◽  
Energy Decomposition Analysis ◽  
Energy Assessment ◽  
Dynamics Simulations ◽  
Positively Charged

Positively charged groups that mimic arginine or lysine in a natural substrate of trypsin are necessary for drugs to inhibit the trypsin-like serine protease TMPRSS2 that is involved in the viral entry and spread of coronaviruses, including SARS-CoV-2. Based on this assumption, we identified a set of 13 approved or clinically investigational drugs with positively charged guanidinobenzoyl and/or aminidinobenzoyl groups, including the experimentally verified TMPRSS2 inhibitors Camostat and Nafamostat. Molecular docking using the C-I-TASSER-predicted TMPRSS2 catalytic domain model suggested that the guanidinobenzoyl or aminidinobenzoyl group in all the drugs could form putative salt bridge interactions with the side-chain carboxyl group of Asp435 located in the S1 pocket of TMPRSS2. Molecular dynamics simulations further revealed the high stability of the putative salt bridge interactions over long-time (100 ns) simulations. The molecular mechanics/generalized Born surface area-binding free energy assessment and per-residue energy decomposition analysis also supported the strong binding interactions between TMPRSS2 and the proposed drugs. These results suggest that the proposed compounds, in addition to Camostat and Nafamostat, could be effective TMPRSS2 inhibitors for COVID-19 treatment by occupying the S1 pocket with the hallmark positively charged groups.

scholarly journals Tumbling with a limp: local asymmetry in water's hydrogen bond network and its consequences

2020 ◽  
Vol 22 (19) ◽  
pp. 10397-10411 ◽  
Author(s):  
Hossam Elgabarty ◽  
Thomas D. Kühne
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Liquid Water ◽  
Decomposition Analysis ◽  
Energy Decomposition Analysis ◽  
Water Molecules ◽  
Hydrogen Bond Network ◽  
Energy Decomposition ◽  
Bond Network ◽  
Dynamics Simulations

Ab initio molecular dynamics simulations of ambient liquid water and energy decomposition analysis have recently shown that water molecules exhibit significant asymmetry between the strengths of the two donor and/or the two acceptor interactions.

scholarly journals Identifying the Hot Spot Residues of the SARS-CoV-2 Main Protease Using MM-PBSA and Multiple Force Fields

Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 54
Author(s):  
Jinyoung Byun ◽  
Juyong Lee
Keyword(s):  
Ligand Binding ◽  
Force Fields ◽  
Binding Free Energy ◽  
Hot Spot ◽  
Decomposition Analysis ◽  
Md Simulations ◽  
Energy Decomposition Analysis ◽  
Energy Calculation ◽  
Binding Affinities ◽  
Main Protease

In this study, we investigated the binding affinities between the main protease of SARS-CoV-2 virus (Mpro) and its various ligands to identify the hot spot residues of the protease. To benchmark the influence of various force fields on hot spot residue identification and binding free energy calculation, we performed MD simulations followed by MM-PBSA analysis with three different force fields: CHARMM36, AMBER99SB, and GROMOS54a7. We performed MD simulations with 100 ns for 11 protein–ligand complexes. From the series of MD simulations and MM-PBSA calculations, it is identified that the MM-PBSA estimations using different force fields are weakly correlated to each other. From a comparison between the force fields, AMBER99SB and GROMOS54a7 results are fairly correlated while CHARMM36 results show weak or almost no correlations with the others. Our results suggest that MM-PBSA analysis results strongly depend on force fields and should be interpreted carefully. Additionally, we identified the hot spot residues of Mpro, which play critical roles in ligand binding through energy decomposition analysis. It is identified that the residues of the S4 subsite of the binding site, N142, M165, and R188, contribute strongly to ligand binding. In addition, the terminal residues, D295, R298, and Q299 are identified to have attractive interactions with ligands via electrostatic and solvation energy. We believe that our findings will help facilitate developing the novel inhibitors of SARS-CoV-2.

scholarly journals BAl4Mg−/0/+: Global Minima with a Planar Tetracoordinate or Hypercoordinate Boron Atom

Atoms ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 89
Author(s):  
Maya Khatun ◽  
Saikat Roy ◽  
Sandip Giri ◽  
Sasanka Sankhar Reddy CH ◽  
Anakuthil Anoop ◽  
...  
Keyword(s):  
Electron Affinity ◽  
Global Minimum ◽  
Chemical Space ◽  
Search Algorithm ◽  
Decomposition Analysis ◽  
Ab Initio Molecular Dynamics ◽  
Stationary Points ◽  
Energy Decomposition Analysis ◽  
Dynamics Simulations ◽  
Bonding Patterns

We have explored the chemical space of BAl4Mg−/0/+ for the first time and theoretically characterized several isomers with interesting bonding patterns. We have used chemical intuition and a cluster building method based on the tabu-search algorithm implemented in the Python program for aggregation and reaction (PyAR) to obtain the maximum number of possible stationary points. The global minimum geometries for the anion (1a) and cation (1c) contain a planar tetracoordinate boron (ptB) atom, whereas the global minimum geometry for the neutral (1n) exhibits a planar pentacoordinate boron (ppB) atom. The low-lying isomers of the anion (2a) and cation (3c) also contain a ppB atom. The low-lying isomer of the neutral (2n) exhibits a ptB atom. Ab initio molecular dynamics simulations carried out at 298 K for 2000 fs suggest that all isomers are kinetically stable, except the cation 3c. Simulations carried out at low temperatures (100 and 200 K) for 2000 fs predict that even 3c is kinetically stable, which contains a ppB atom. Various bonding analyses (NBO, AdNDP, AIM, etc.) are carried out for these six different geometries of BAl4Mg−/0/+ to understand the bonding patterns. Based on these results, we conclude that ptB/ppB scenarios are prevalent in these systems. Compared to the carbon counter-part, CAl4Mg−, here the anion (BAl4Mg−) obeys the 18 valence electron rule, as B has one electron fewer than C. However, the neutral and cation species break the rule with 17 and 16 valence electrons, respectively. The electron affinity (EA) of BAl4Mg is slightly higher (2.15 eV) than the electron affinity of CAl4Mg (2.05 eV). Based on the EA value, it is believed that these molecules can be identified in the gas phase. All the ptB/ppB isomers exhibit π/σ double aromaticity. Energy decomposition analysis predicts that the interaction between BAl4−/0/+ and Mg is ionic in all these six systems.

Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease

2014 ◽  
Vol 92 (5) ◽  
pp. 357-369 ◽  
Author(s):  
Huiqun Wang ◽  
Lingling Geng ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Computational Study ◽  
Decomposition Analysis ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Energy Decomposition Analysis ◽  
Free Energy Decomposition

Narlaprevir is a novel NS3/4A protease inhibitor of hepatitis C virus (HCV), and it has been tested in a phase II clinical trial recently. However, distinct drug-resistance of Narlaprevir has been discovered. In our study, the molecular mechanisms of drug-resistance of Narlaprevir due to the mutations V36M, R155K, V36M+R155K, T54A, and A156T of NS3/4A protease have been investigated by molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energies of Narlaprevir towards the wild-type and five mutants show that the mutations V36M, R155K, and T54A lead to low-level drug resistance and the mutations V36M+R155K and A156T lead to high-level drug resistance, which is consistent with the experimental data. The analysis of the individual energy terms indicates that the van der Waals contribution is important for distinguishing the binding affinities of these six complexes. These findings again show that the combination of different molecular modeling techniques is an efficient way to interpret the molecular mechanism of drug-resistance. Our work mainly elaborates the molecular mechanism of drug-resistance of Narlaprevir and further provides valuable information for developing novel, safer, and more potent HCV antiviral drugs in the near future.

Vapour Pressure Isotope Effect on Evaporation from Pure Organic Phases - a PIMD Approach

2020 ◽  
Author(s):  
Luis Vasquez ◽  
Agnieszka Dybala-Defratyka
Keyword(s):  
Path Integral ◽  
Vapour Pressure ◽  
Density Functional ◽  
Isotope Effects ◽  
Tight Binding ◽  
Decomposition Analysis ◽  
Energy Decomposition Analysis ◽  
Special Importance ◽  
Non Covalent Interactions ◽  
Covalent Interactions

<p></p><p>Very often in order to understand physical and chemical processes taking place among several phases fractionation of naturally abundant isotopes is monitored. Its measurement can be accompanied by theoretical determination to provide a more insightful interpretation of observed phenomena. Predictions are challenging due to the complexity of the effects involved in fractionation such as solvent effects and non-covalent interactions governing the behavior of the system which results in the necessity of using large models of those systems. This is sometimes a bottleneck and limits the theoretical description to only a few methods.<br> In this work vapour pressure isotope effects on evaporation from various organic solvents (ethanol, bromobenzene, dibromomethane, and trichloromethane) in the pure phase are estimated by combining force field or self-consistent charge density-functional tight-binding (SCC-DFTB) atomistic simulations with path integral principle. Furthermore, the recently developed Suzuki-Chin path integral is tested. In general, isotope effects are predicted qualitatively for most of the cases, however, the distinction between position-specific isotope effects observed for ethanol was only reproduced by SCC-DFTB, which indicates the importance of using non-harmonic bond approximations.<br> Energy decomposition analysis performed using the symmetry-adapted perturbation theory (SAPT) revealed sometimes quite substantial differences in interaction energy depending on whether the studied system was treated classically or quantum mechanically. Those observed differences might be the source of different magnitudes of isotope effects predicted using these two different levels of theory which is of special importance for the systems governed by non-covalent interactions.</p><br><p></p>

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