scholarly journals Influence of Mg2+ ions on the interaction between 3,5-dicaffeoylquinic acid and HTLV-I integrase

2012 ◽  
Vol 17 (1) ◽  
pp. 5 ◽  
Author(s):  
Ángela Peña ◽  
Juvenal Yosa ◽  
Yesid Cuesta-Astroz ◽  
Orlando Acevedo ◽  
Leonardo Lareo ◽  
...  
Keyword(s):  
Free Energy ◽  
Rational Design ◽  
Catalytic Domain ◽  
Binding Free Energy ◽  
Homology Model ◽  
Binding Mode ◽  
Antiretroviral Drugs ◽  
Type I ◽  
Interaction Sites ◽  
Dicaffeoylquinic Acid

<strong>Objective</strong>. Using molecular simulation, we studied the influence of Mg2+ ions on the binding mode of HTLV-I Integrase (IN) catalytic domain (modeled by homology) with the 3,5- Dicaffeoylquinic Acid (DCQA). HTLV-I Integrase homology model was built using template-like crystallographic data of the IN catalytic domain solved for Avian Sarcoma Virus (VSA, pdb: 1VSD). <strong>Materials and</strong> <strong>methods</strong>. In order to analyze the role of Mg2+ in the interaction or coupling between 3,5-DCQA and Integrase, three models were created: i) in the absence of Mg2+ ions, ii) with a Mg2+ ion coordinated at Asp15 and Asp72 and iii) model with two Mg2+ ions coordinated at Asp15-Asp72 and Asp72-Glu108. Coupling force and binding free energy between 3,5-DCQA and HTLV-I IN were assessed in the three models. <strong>Results</strong>. The lowest docking score and free energy binding were obtained for the second model. Mg2+ ion strongly affected the coupling of the inhibitor 3,5-DCQA with HTLV-I catalytic domain of Integrase, thus revealing a strong interaction in the ligand-protein complex regardless of the ligand-catalytic interaction sites for all three models. <strong>Conclusion</strong>. Altogether, these results strengthen the hypothesis that the presence of one Mg2+ ion could enhance the interaction in the complex by decreasing free energy, therefore increasing the affinity. Moreover, we propose 3, 5-DCQA as an important pharmacophore in the rational design of new antiretroviral drugs.<br /><br /><strong>Key words</strong>: 3,5 -Dicaffeoylquinic Acid, Human T-Lymphotropic Type I (HTLV-1), Integrase (IN), Homology Model, Molecular Docking, Binding Free Energy, Mg2+ Ions.

scholarly journals Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations

2017 ◽  
Vol 114 (11) ◽  
pp. E2136-E2145 ◽  
Author(s):  
Federica Moraca ◽  
Jussara Amato ◽  
Francesco Ortuso ◽  
Anna Artese ◽  
Bruno Pagano ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Rational Design ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Dna Interaction ◽  
Accurate Estimate ◽  
Binding Modes ◽  
Binding Mechanism ◽  
Promoter Regions

G-quadruplexes (G4s) are higher-order DNA structures typically present at promoter regions of genes and telomeres. Here, the G4 formation decreases the replicative DNA at each cell cycle, finally leading to apoptosis. The ability to control this mitotic clock, particularly in cancer cells, is fascinating and passes through a rational understanding of the ligand/G4 interaction. We demonstrate that an accurate description of the ligand/G4 binding mechanism is possible using an innovative free-energy method called funnel-metadynamics (FM), which we have recently developed to investigate ligand/protein interaction. Using FM simulations, we have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 (d[AG3(T2AG3)3]), computing also the binding free-energy landscape. Two ligand binding modes have been identified as the lowest energy states. Furthermore, we have found prebinding sites, which are preparatory to reach the final binding mode. In our simulations, the ions and the water molecules have been explicitly represented and the energetic contribution of the solvent during ligand binding evaluated. Our theoretical results provide an accurate estimate of the absolute ligand/DNA binding free energy (ΔGb0 = −10.3 ± 0.5 kcal/mol) that we validated through steady-state fluorescence binding assays. The good agreement between the theoretical and experimental value demonstrates that FM is a most powerful method to investigate ligand/DNA interaction and can be a useful tool for the rational design also of G4 ligands.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations

2016 ◽  
Vol 12 (4) ◽  
pp. 1174-1182 ◽  
Author(s):  
Liang Fang ◽  
Xiaojian Wang ◽  
Meiyang Xi ◽  
Tianqi Liu ◽  
Dali Yin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Model Building ◽  
Binding Free Energy ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Selectivity ◽  
Sphingosine Kinases ◽  
Binding Free Energy Calculations

Three residues of SK1 were identified important for selective SK1 inhibitory activity via SK2 homology model building, molecular dynamics simulation, and MM-PBSA studies.

scholarly journals Solvents to Fragments to Drugs: MD Applications in Drug Design

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3269 ◽  
Author(s):  
Lucas Defelipe ◽  
Juan Arcon ◽  
Carlos Modenutti ◽  
Marcelo Marti ◽  
Adrián Turjanski ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Mixed Solvents ◽  
Md Simulations ◽  
Binding Mode ◽  
Condensed State ◽  
Protein Targets ◽  
Drug Candidates ◽  
Interaction Sites ◽  
Aqueous Solvation ◽  
The Common

Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates.

scholarly journals Interaction of Coumarin Phytoestrogens with ERα and ERβ: A Molecular Dynamics Simulation Study

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1165 ◽  
Author(s):  
Ting Wang ◽  
Yunfei Wang ◽  
Xuming Zhuang ◽  
Feng Luan ◽  
Chunyan Zhao ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Human Life ◽  
Simulation Method ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Molecular Dynamics Methods ◽  
17Β Estradiol ◽  
The Stability

Coumarin phytoestrogens, as one of the important classes of phytoestrogens, have been proved to play an important role in various fields of human life. In this study, molecular simulation method including molecular docking and molecular dynamics methods were performed to explore the various effects between four classical coumarin phytoestrogens (coumestrol, 4-methoxycoumestrol, psoralen and isopsoralen), and estrogen receptors (ERα, ERβ), respectively. The calculated results not only proved that the four coumarin phytoestrogens have weaker affinity than 17β-estradiol to both ERα, and ERβ, but also pointed out that the selective affinity for ERβ is greater than ERα. In addition, the binding mode indicated that the formation of hydrogen bond and hydrophobic interaction have an important effect on the stability of the complexes. Further, the calculation and decomposition of binding free energy explored the main contribution interactions to the total free energy.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

scholarly journals The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts

2009 ◽  
Vol 143 (3) ◽  
pp. 111-123 ◽  
Author(s):  
Martin Spichty ◽  
Antoine Taly ◽  
Franz Hagn ◽  
Horst Kessler ◽  
Sofia Barluenga ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Chemical Shifts ◽  
Binding Mode

scholarly journals The ‘natural’ hybrid haemoglobin from mule. Interrelationships with its parent haemoglobins from horse and donkey

1992 ◽  
Vol 282 (2) ◽  
pp. 595-599 ◽  
Author(s):  
S G Condò ◽  
M Coletta ◽  
R Cicchetti ◽  
G Argentin ◽  
P Guerrieri ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Natural Hybrid ◽  
Binding Properties ◽  
Inositol Hexakisphosphate ◽  
Physiological Conditions ◽  
General Terms ◽  
O2 Binding

The equilibrium O2-binding properties of the hybrid haemoglobin (Hb) present in vivo in erythrocytes from mule and of its parent Hbs from horse and donkey were compared with special reference to the effect of heterotropic ligands such as Cl-, D-glycerate 2,3-bisphosphate (DPG) and inositol hexakisphosphate. All these Hbs display a decreased effect by polyphosphates, confirming that what has been observed for horse Hb [Giardina, Brix, Clementi, Scatena, Nicoletti, Cicchetti, Argentin & Condò (1990) Biochem. J. 266, 897-900] is common to other equine species, at least from a qualitative standpoint. However, different quantitative aspects can be detected, which can be accounted for by a different role for the two types of chain in characterizing the binding free energy for the various heterotropic effectors. In particular, it is shown that the binding mode of DPG and inositol hexakisphosphate displays different features since long-range effects can be observed clearly for inositol hexakisphosphate but not for DPG. In general terms, in spite of a different intrinsic O2 affinity, the modulation of functional properties by third ligands leads these Hbs to behave, under physiological conditions, similarly to human HbA. It might represent an interesting example of how different species with similar functional needs find different ways to produce a similar functional behaviour.

scholarly journals A Drug Repurposing Approach to Identify Therapeutics by Screening Medicines for Malaria Ventures Exploiting SARS-CoV-2 Main Protease

2021 ◽  
Author(s):  
Rashmi Tyagi ◽  
Anubrata Paul ◽  
V. Samuel Raj ◽  
Krishna Kumar Ojha ◽  
Manoj Kumar Yadav
Keyword(s):  
Free Energy ◽  
Catalytic Domain ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Energy Calculation ◽  
High Morbidity ◽  
Molecular Docking Study ◽  
Virus Propagation ◽  
Main Protease

<p>COVID-19 pandemic makes the human-kind standstill and results in high morbidity and mortality cases worldwide. Still, there are no approved antiviral drugs with proven efficacy nor any therapeutic vaccines to combat the disease as per the current date. In the present study, SARS-CoV-2 main protease (Mpro) has been taken as a potential drug target considering its crucial role in virus propagation. We have used 400 diverse bioactive inhibitors with proven antibacterial and antiviral properties for screening against Mpro target. Our screening result identifies ten compounds with higher binding affinity than N3 (used as a reference compound to validate the experiment). All the compounds possess desire physicochemical properties. Later on, in-depth docking and superimposition of selected complexes confirm that only three compounds (MMV1782211, MMV1782220 and MMV1578574) are actively interacting with the catalytic domain of Mpro. </p> <p>Furthermore, the selected three molecules complexed with Mpro and N3-Mpro as control are subjected to molecular dynamics simulation study (root means square deviation, root mean square fluctuation, hydrogen bonding, solvent-accessible area and radius of gyration). MMV1782211-Mpro complex shows a strong and stable interaction as compared to others. The MM/PBSA free energy calculation shows the highest binding free energy of –115.8 kJ/mol for MMV1782211 compound also cross-confirms our molecular docking study. Therefore, our <i>in silico</i> findings become very interesting towards developing alternative medicine against SARS-CoV-2 Mpro target. So, we can expect prompt actions in this direction to combat the COVID-19.</p>

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