scholarly journals Molecular interpretation of the carbon nitride performance as a template for the transport of anti-cancer drug into the biological membrane

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ameneh Zaboli ◽  
Heidar Raissi ◽  
Farzaneh Farzad
Keyword(s):  
Free Energy ◽  
Carbon Nitride ◽  
Md Simulation ◽  
Molecular Design ◽  
Biological Membrane ◽  
Interaction Mechanism ◽  
Free Energy Calculations ◽  
Electrostatic Energy ◽  
Cancer Drug ◽  
Free Energy Surface

AbstractEvaluation of interaction mechanism between 2-dimensional (2D) nanomaterials and cell membranes is a critical issue in providing guidelines for biomedical applications. Recent progress in computer-aided molecular design tools, especially molecular dynamics (MD) simulation, afford a cost-effective approach to achieving this goal. In this work, based on this hypothesis, by utilizing theoretical methods including MD simulation and free energy calculations, a process is evaluated in which the Doxorubicin (DOX)-loaded onto carbon nitride (CN) nanosheet faced with bilayer membrane. It should be mentioned that to achieve an efficient CN-based drug delivery system (DDS), in the first place, the intermolecular interaction between the carrier and DOX is investigated. The obtained results show that the DOX prefers a parallel orientation with respect to the CN surface via the formation of π–π stacking and H-bond interactions. Furthermore, the adsorption energy value between the drug and the carrier is evaluated at about − 312 kJ/mol. Moreover, the investigation of the interaction between the CN-DOX complex and the membrane reveals that due to the presence of polar heads in the lipid bilayer, the contribution of electrostatic energy is higher than the van der Waals energy. The global minimum in free energy surface of the DDS is located between the head groups of the cell membrane. Overall, it can be concluded that the CN nanosheet is a suitable candidate for transfer and stabilize DOX on the membrane.

scholarly journals An Asymmetric Mechanism in a Symmetric Molecular Machine

2020 ◽  
Author(s):  
Florian Blanc ◽  
Marco Cecchini
Keyword(s):  
Free Energy ◽  
Large Scale ◽  
Technological Development ◽  
Thermal Fluctuations ◽  
Free Energy Calculations ◽  
Molecular Machine ◽  
Free Energy Surface ◽  
Promising Area ◽  
Sequential Mechanism ◽  
External Stimuli

The design of molecular architectures exhibiting functional motions is a promising area for disruptive technological development. Towards this goal, rotaxanes and catenanes, which undergo relative motions of their sub-units in response to external stimuli, are prime candidates. Here, we report on the computational analysis of the contraction/extension of a bistable [c2]-daisy chain rotaxane. Using free energy calculations and transition path optimizations, we explore the free energy landscape governing the functional motions of a prototypical molecular machine with atomic resolution.<br>The calculations reveal a sequential mechanism for contraction/extension in which the asynchronous gliding of each ring is preferred over the concerted movement suggested by chemical intuition. Analysis of the underlying free energy surface indicates that dissymmetric gliding is favored because it entails crossings of much smaller barriers.<br>Our findings illustrate an important design principle for molecular machines, namely that efficient exploitation of thermal fluctuations may be realized by breaking down the large-scale functional motions into smaller steps.

scholarly journals An Asymmetric Mechanism in a Symmetric Molecular Machine

2020 ◽  
Author(s):  
Florian Blanc ◽  
Marco Cecchini
Keyword(s):  
Free Energy ◽  
Large Scale ◽  
Technological Development ◽  
Thermal Fluctuations ◽  
Free Energy Calculations ◽  
Molecular Machine ◽  
Free Energy Surface ◽  
Promising Area ◽  
Sequential Mechanism ◽  
External Stimuli

The design of molecular architectures exhibiting functional motions is a promising area for disruptive technological development. Towards this goal, rotaxanes and catenanes, which undergo relative motions of their sub-units in response to external stimuli, are prime candidates. Here, we report on the computational analysis of the contraction/extension of a bistable [c2]-daisy chain rotaxane. Using free energy calculations and transition path optimizations, we explore the free energy landscape governing the functional motions of a prototypical molecular machine with atomic resolution.<br>The calculations reveal a sequential mechanism for contraction/extension in which the asynchronous gliding of each ring is preferred over the concerted movement suggested by chemical intuition. Analysis of the underlying free energy surface indicates that dissymmetric gliding is favored because it entails crossings of much smaller barriers.<br>Our findings illustrate an important design principle for molecular machines, namely that efficient exploitation of thermal fluctuations may be realized by breaking down the large-scale functional motions into smaller steps.

Free Energy Calculations in Molecular Design: Predictions by Theory and Reality by Experiment with Enantioselective Podand Ionophores

1994 ◽  
Vol 116 (8) ◽  
pp. 3593-3594 ◽  
Author(s):  
Matthew T. Burger ◽  
Alan Armstrong ◽  
Frank Guarnieri ◽  
D. Quentin McDonald ◽  
W. Clark Still
Keyword(s):  
Free Energy ◽  
Molecular Design ◽  
Free Energy Calculations ◽  
Energy Calculations

scholarly journals SARS-CoV-2 host cell entry: an in silico investigation of potential inhibitory roles of terpenoids

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gideon A. Gyebi ◽  
Oludare M. Ogunyemi ◽  
Ibrahim M. Ibrahim ◽  
Olalekan B. Ogunro ◽  
Adegbenro P. Adegunloye ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Cell Entry ◽  
Spike Protein ◽  
Energy Calculations ◽  
Wide Range ◽  
Binding Free Energy Calculations

Abstract Background Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2), and the spike (S) proteins of SARS-CoV-2, SARS-CoV, and MERS-CoV. In silico absorption-distribution-metabolism-excretion-toxicity (ADMET) and drug-likeness prediction, molecular dynamics (MD) simulation, binding free energy calculations, and clustering analysis of MD simulation trajectories were performed on the top docked terpenoids to respective protein targets. Results The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Two pentacyclic terpenoids (24-methylene cycloartenol and isoiguesteri) interacted with the hACE2 binding hotspots for the SARS-CoV-2 spike protein, while the abietane diterpenes were found accommodated within the S1-specificity pocket, interacting strongly with the active site residues TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. These interactions were preserved in a simulated dynamic environment, thereby, demonstrating high structural stability. The MM-GBSA binding free energy calculations corroborated the docking interactions. The top docked terpenoids showed favorable drug-likeness and ADMET properties over a wide range of molecular descriptors. Conclusion The identified terpenoids from this study provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell-mediated entry proteins. They are therefore recommended for further in vitro and in vivo studies towards developing entry inhibitors against the ongoing COVID-19 pandemic.

scholarly journals Investigation of Molecular Modeling And Molecular Dynamics Simulation In BRCA-1 And BRCA-2 Genes of Amygdalin Ligand

2021 ◽  
Author(s):  
Erkan ÖNER ◽  
Ilter demirhan ◽  
Arabinda GHOSH ◽  
Meltem GUNGOR ◽  
Ali Erdinc YALIN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Free Energy ◽  
Md Simulation ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Cancer Drug ◽  
Active Inhibitor ◽  
Brca 1 ◽  
Brca 2

Abstract Breast cancer is the most common type of cancer and the most fatal type among women. BRCA-1 and BRCA-2 are tumor suppressor genes known to cause breast cancer. Drug studies have become very important to target the production of more accurate drugs by reducing the cost with the previous designs of drugs in this field. Amygdalin is used in the treatment of especially cancer, characterized by the loss of red blood cell production. In this study, which was conducted for the first time, it was aimed to examine the use of amygdalin in breast cancer treatment by coupling to the active regions of BRCA-1 and BRCA-2 genes by molecular docking method. The best attachment scores were selected. Amygdalin was taken from PubChem database in sdf format. According to the molecular insertion results, the free energy of the amygdalin ligand for binding to the BRCA-1 protein was -4.8 kcal/mol and the free energy for binding to the BRCA-2 protein was -7.2 kcal/mol also include Ki values. MD simulation was performed using Desmond. Insertion results show that the amygdalin ligand binds more strongly to the BRCA-2 protein than to the BRCA-1 protein. MD simulation for the highly active inhibitor Amigydalin in complex with protein BRCA-2 revealed that the stabilization of ligand was achieved due to the formation of uninterrupted hydrophobic interactions. Due to the binding power of amygdalin ligand, it reveals a unique structure for breast cancer and it is thought to be a reference for designing new molecules with the same structure against cancer and applying these molecules in vivo and in vitro studies.

scholarly journals Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study

2020 ◽  
Author(s):  
Junmei Wang
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Binding Free Energy ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Free Energy Calculations ◽  
Rational Drug Design ◽  
Cancer Drug ◽  
Receptor Ligand ◽  
Charged Form

<p>The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. Taking the advantage of a recently released crystal structure of COVID-19 protease in complex with a covalently-bonded inhibitor, N3,<sup>1</sup> I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS.<sup>2-4</sup> Several promising known drugs stand out as potential inhibitors of COVID-19 protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.82 kcal/mol. Streptomycin, an antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.82 kcal/mol) is not nearly as low as that of the neutral form (-7.92 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.86 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including COVID-19, SARS, MERS, and HCV. The findings of this study can facilitate rational drug design targeting the COVID-19 protease.</p><p> </p>

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