Molecular Modeling Approach to Investigate the Intercalation of Phthalates and Their Metabolites in DNA Macromolecules

2019 ◽  
Vol 16 (2) ◽  
pp. 373-380 ◽  
Author(s):  
Tatiane P. Rodrigues ◽  
Jorddy N. Cruz ◽  
Tiago S. Arouche ◽  
Tais S. S. Pereira ◽  
Wanessa A. Costa ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Van Der Waals ◽  
Genetic Material ◽  
Ligand Interaction ◽  
Dynamics Simulations

Recent studies have reported that phthalates are capable of causing mutations and other changes in the genetic material. This study aimed to investigate the molecular interactions between phthalate di(2-ethylhexyl) phthalate (DEHP) and its metabolites monobutyl phthalate (MBP) and monoethyl phthalate (MEP), interacting with DNA. The research was conducted using molecular modeling techniques such as molecular docking and molecular dynamics simulations. Molecular docking revealed that the DEHP, MBP, and MEP are able to establish hydrogen interactions with various nucleotide bases. Molecular dynamics simulations revealed that these molecules interacted with the DNA, and the binding free energy results demonstrated that the DNA-ligand interaction has favorable free energy. The values for free binding energy were as follows: DNA–DEHP, –21.66 kcal/mol; DNA–MBP, –17.29 kcal/mol; and DNA–MEP, –20.13 kcal/mol. For these three systems, the contributions of van der Waals, electrostatic, and nonpolar solvation energy were favorable for the interaction. The van der Waals interactions contributed the major energy to the intercalation of the binders.

The Interaction of Isoflavone Phytoestrogens with ERα and ERβ by Molecular Docking and Molecular Dynamics Simulations

2020 ◽  
Vol 16 ◽  
Author(s):  
Ting Wang ◽  
Yaquan Liu ◽  
Xuming Zhuang ◽  
Feng Luan ◽  
Chunyan Zhao
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Estrogen Receptors ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Docking Studies ◽  
The Body ◽  
Factors Affecting ◽  
Dynamics Simulations

Aim and Objective: Isoflavone phytoestrogens, which commonly present in natural plants, are closely related to human health. The combination of them with estrogen receptors in the body can play a more important role in the prevention and treatment of cardiovascular diseases, cancer, and menopausal diseases. This research is conducted for the wider application of isoflavone phytoestrogens in various fields. Method: In this study, molecular docking studies and molecular dynamics simulations were performed to explore the affinities and interaction between three typical isoflavone phytoestrogens and estrogen receptors (ERα and ERβ), respectively. Results and Conclusion: Molecular docking results showed that the affinity of genistein, daidzein and formononetin was different, and the ligand structures and hydrogen bonds force were the main factors affecting the binding abilities. The calculation of the binding free energy shows the stability of the complex and the contribution of various interactions to the binding free energy. The decomposition of binding free energy indicates that van der Waals interaction and electrostatic interaction promote the binding of the complex, which are in agreement with the docking studies.

scholarly journals Elucidating Biophysical Basis of Binding of Inhibitors to SARS-CoV-2 Main Protease by Using Molecular Dynamics Simulations and Free Energy Calculations

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Rajarshi Roy ◽  
Nisha Amarnath Jonniya ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Van Der Waals ◽  
Antiviral Drug ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Main Protease ◽  
Dynamics Simulations

<div>The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly</div><div>worldwide, causing a global pandemic. In the absence of a vaccine or a suitable</div><div>chemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight this</div><div>deadly respiratory disease. In the present work, we have elucidated the mechanism of binding</div><div>of two inhibitors, namely α-ketoamide and Z31792168 to SARS-CoV-2 main protease (Mpro</div><div>or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We</div><div>calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed</div><div>ΔGbind into various forces governing the complex formation using the Molecular</div><div>Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal</div><div>that α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= -</div><div>3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to</div><div>Z31792168 arises due to an increase in the favorable electrostatic and van der Waals</div><div>interactions between the inhibitor and 3CLpro. Further, we have identified important residues</div><div>controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free</div><div>energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral</div><div>drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared</div><div>to both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the van der</div><div>Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On</div><div>the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic</div><div>and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our</div><div>study might help in designing rational anticoronaviral drugs targeting the SARS-CoV-2 main</div><div>protease. </div>

scholarly journals Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

2020 ◽  
Author(s):  
Dr. Chirag N. Patel ◽  
Dr. Prasanth Kumar S. ◽  
Dr. Himanshu A. Pandya ◽  
Dr. Rakesh M. Rawal
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculations ◽  
Dynamics Simulations

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>

scholarly journals Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

2020 ◽  
Author(s):  
Dr. Chirag N. Patel ◽  
Dr. Prasanth Kumar S. ◽  
Dr. Himanshu A. Pandya ◽  
Dr. Rakesh M. Rawal
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Energy Calculations ◽  
Dynamics Simulations

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>

scholarly journals Elucidating Biophysical Basis of Binding of Inhibitors to SARS-CoV-2 Main Protease by Using Molecular Dynamics Simulations and Free Energy Calculations

2020 ◽  
Author(s):  
Md Fulbabu Sk ◽  
Rajarshi Roy ◽  
Nisha Amarnath Jonniya ◽  
Sayan Poddar ◽  
Parimal Kar
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Van Der Waals ◽  
Antiviral Drug ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Main Protease ◽  
Dynamics Simulations

<div>The recent outbreak of novel “coronavirus disease 2019” (COVID-19) has spread rapidly</div><div>worldwide, causing a global pandemic. In the absence of a vaccine or a suitable</div><div>chemotherapeutic intervention, it is an urgent need to develop a new antiviral drug to fight this</div><div>deadly respiratory disease. In the present work, we have elucidated the mechanism of binding</div><div>of two inhibitors, namely α-ketoamide and Z31792168 to SARS-CoV-2 main protease (Mpro</div><div>or 3CLpro) by using all-atom molecular dynamics simulations and free energy calculations. We</div><div>calculated the total binding free energy (ΔGbind) of both inhibitors and further decomposed</div><div>ΔGbind into various forces governing the complex formation using the Molecular</div><div>Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Our calculations reveal</div><div>that α-ketoamide is more potent (ΔGbind= - 9.05 kcal/mol) compared to Z31792168 (ΔGbind= -</div><div>3.25 kcal/mol) against COVID-19 3CLpro. The increase in ΔGbind for α-ketoamide relative to</div><div>Z31792168 arises due to an increase in the favorable electrostatic and van der Waals</div><div>interactions between the inhibitor and 3CLpro. Further, we have identified important residues</div><div>controlling the 3CLpro-ligand binding from per-residue based decomposition of the binding free</div><div>energy. Finally, we have compared ΔGbind of these two inhibitors with the anti-HIV retroviral</div><div>drugs, such as lopinavir and darunavir. It is observed that α-ketoamide is more potent compared</div><div>to both lopinavir and darunavir. In the case of lopinavir, a decrease in the size of the van der</div><div>Waals interactions is responsible for the lower binding affinity compared to α-ketoamide. On</div><div>the other hand, in the case of darunavir, a decrease in the favorable intermolecular electrostatic</div><div>and van der Waals interactions contributes to lower affinity compared to α-ketoamide. Our</div><div>study might help in designing rational anticoronaviral drugs targeting the SARS-CoV-2 main</div><div>protease. </div>

Understanding the selectivity of inhibitors toward PI4KIIIα and PI4KIIIβ based molecular modeling

2019 ◽  
Vol 21 (39) ◽  
pp. 22103-22112 ◽  
Author(s):  
Shuaizhen Tian ◽  
Jinzhe Zeng ◽  
Xiao Liu ◽  
Jianzhong Chen ◽  
John Z. H. Zhang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Modeling ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations ◽  
Phosphatidylinositol 4

Molecular dynamics simulations and binding free energy calculations are combined to investigate the selectivity of inhibitors toward type III phosphatidylinositol 4 kinases.

scholarly journals Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 998
Author(s):  
Yorley Duarte ◽  
Maximiliano Rojas ◽  
Jonathan Canan ◽  
Edwin G. Pérez ◽  
Fernando González-Nilo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Ion Channel ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr ◽  
Dynamics Simulations

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion−channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion−channel.

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