scholarly journals ZIKA VIRUS SERENE PROTEASE COMPLEX (NS2B-NS3) INHIBITION BY 2-AMINO-5-{[(1Z)-AMINO({[(Z)-BENZOYL]IMINO})METHYL]AMINO}-N-(5-AMINO-7-{[CARBAMOYL(PHENYL)METHYL]AMINO}-6-OXOHEPTYL)PENTANAMIDE, IN SILICO STUDIES

2017 ◽  
Vol 10 (5) ◽  
pp. 210
Author(s):  
Kalpana Virendra Singh ◽  
Ramchander Merugu ◽  
Jeeven Singh Solanki
Keyword(s):  
Free Energy ◽  
Serine Protease ◽  
Zika Virus ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Free Energy Calculations ◽  
Protease Inhibition ◽  
Docking Simulations ◽  
In Silico Studies ◽  
Ns3 Protease

Objective: The present in silico study is taken to report 2-amino-5-{[(1Z) -amino ({[(Z) -benzoyl] imino}) methyl] amino} -N-(5-amino-7-{[carbamoyl (phenyl) methyl] amino} -6-oxoheptyl) pentanamide as Zika virus (ZIKV) NS2B-NS3 protease inhibitor.Methods: In silico studies performed on online docking servers. NS2B-NS3 serine protease from ZIKV with PDB ID: 5GJ4 a hydrolase with total structure weight of 102878.54 is selected as the target. Docking server is used for carrying out docking calculations. Lamarckian genetic algorithm and the Solis and Wets local search methods are used for performing docking simulations. Free energy calculations, hydrogen bond (HB) formation, polar and hydrophobic interactions and HB plot are studied in this study.Results: Binding pocket is found on a serine protease NS2B chain A. Binding site predictions propose NKK as the suitable ligand for binding, which has structure closely related to the proposed ligand2-amino-5-{[(1Z) -amino ({[(Z) -benzoyl] imino}) methyl] amino} -N-(5-amino-7-{[carbamoyl (phenyl) methyl] amino} -6-oxoheptyl) pentanamide. Free energy of binding is - 4.08 kcal/Mol and inhibition constant (Ki) is very less 1.02 mm. The ligand binds to chain A of NS2B and chain B of NS3 serine protease. The legend is bound to serine protease complex through strong HB, formed between THR 60 (A) and N6 of ligand, GLU62 (A) and N8 of ligand, ARG 55 (A) and N3 of ligand and ASN108 (B) and N7 of ligand apart from polar and hydrophobic interactions.Conclusion: Docking studies performed establishes the proposed ligand2-amino-5-{[(1Z)-amino ({[(Z)-benzoyl] imino}) methyl] amino} -N-(5- amino-7-{[carbamoyl (phenyl) methyl] amino}-6-oxoheptyl) pentanamide as a molecule which can be used for the inhibition of ZIKV NS2B-NS3 serine protease.Keywords: Zika virus, NS2B-NS3 protease, Inhibition, In silico.

scholarly journals Computational modeling reveals a hydrophobic force-induced pore-forming mechanism for cholesterol-dependent cytolysins

2019 ◽  
Author(s):  
Shichao Pang ◽  
Junchen Yang ◽  
Jingfang Wang
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Structural Model ◽  
Hydrophobic Interactions ◽  
Free Energy Calculations ◽  
Forming Process ◽  
Hydrophobic Force ◽  
Forming Mechanism ◽  
Hydrophobic Pore ◽  
Dynamics Simulations

ABSTRACTDuring the pore-forming process, cholesterol-dependent cytolysins (CDCs) bind to cholesterol-rich membranes and subsequently undergo a series of conformational changes, predominantly involving in the collapse of the protein and the transformation from α helices to β-hairpins to form a large hydrophobic pore. In the current study, we reconstructed a structural model for both the prepore and pore-forming complexes of PFO based on the cryo-EM data of pneumolysin and performed molecular dynamics simulations and free energy calculations to study the conformational changes in the PFO prepore-to-pore conversion. Our simulations indicate that D2 cannot collapse spontaneously due to the hydrogen bonding and pi-pi interactions between domains D2 and D3, which are partially weakened by binding to cell membranes and oligomerization. The free energy landscape for the prepore-to-pore conversion reveals that an additional force is required for the collapse of D2 to overcome an energy barrier of ∼ 24 kcal/mol. Based on these computational results, we proposed a hydrophobic force-induced pore-forming mechanism to explain the pore-forming process of CDCs. In this mechanism, the hydrophobic interactions between the TMHs and membranes are essential for the prepore-to-pore conversion. The hydrophobic force generated by the TMHs-membrane interactions drives the conformational changes in domains D2 and D3. These findings well explain how the conformational changes within two distant domains synergistically occur, and fits well for the previous biophysical and biochemical data.

scholarly journals Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 707 ◽  
Author(s):  
Eva Martins ◽  
Vera Silva ◽  
Agostinho Lemos ◽  
Andreia Palmeira ◽  
Ploenthip Puthongking ◽  
...  
Keyword(s):  
In Silico ◽  
Crucial Role ◽  
Ex Vivo ◽  
Glycoprotein P ◽  
Docking Simulations ◽  
Knowing That ◽  
P Glycoprotein ◽  
In Silico Studies ◽  
Gp Model

P-glycoprotein (P-gp) plays a crucial role in the protection of susceptible organs, by significantly decreasing the absorption/distribution of harmful xenobiotics and, consequently, their toxicity. Therefore, P-gp has been proposed as a potential antidotal pathway, when activated and/or induced. Knowing that xanthones are known to interact with P-gp, the main goal was to study P-gp induction or/and activation by six new oxygenated xanthones (OX 1-6). Furthermore, the potential protection of Caco-2 cells against paraquat cytotoxicity was also assessed. The most promising compound was further tested for its ability to increase P-gp activity ex vivo, using everted intestinal sacs from adult Wistar-Han rats. The oxygenated xanthones interacted with P-gp in vitro, increasing P-gp expression and/or activity 24 h after exposure. Additionally, after a short-incubation period, several xanthones were identified as P-gp activators, as they immediately increased P-gp activity. Moreover, some xanthones decreased PQ cytotoxicity towards Caco-2 cells, an effect prevented under P-gp inhibition. Ex vivo, a significant increase in P-gp activity was observed in the presence of OX6, which was selectively blocked by a model P-gp inhibitor, zosuquidar, confirming the in vitro results. Docking simulations between a validated P-gp model and the tested xanthones predicted these interactions, and these compounds also fitted onto previously described P-gp induction and activation pharmacophores. In conclusion, the in vitro, ex vivo, and in silico results suggest the potential of some of the oxygenated xanthones in the modulation of P-gp, disclosing new perspectives in the therapeutics of intoxications by P-gp substrates.

In-silico Methods of Drug Design: Molecular Simulations and Free Energy Calculations

2019 ◽  
pp. 521-533 ◽  
Author(s):  
Fortunatus Chidolue Ezebuo ◽  
Prem P. Kushwaha ◽  
Atul K. Singh ◽  
Shashank Kumar ◽  
Pushpendra Singh
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
In Silico ◽  
Molecular Simulations ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
In Silico Methods

scholarly journals IN VITRO AND IN SILICO EVALUATION OF XANTHINE OXIDASE INHIBITORY ACTIVITY OF QUERCETIN CONTAINED IN SONCHUS ARVENSIS LEAF EXTRACT

2017 ◽  
Vol 10 (14) ◽  
pp. 50
Author(s):  
Rini Hendriani ◽  
Nursamsiar Nursamsiar ◽  
Ami Tjitraresmi
Keyword(s):  
Free Energy ◽  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Leaf Extract ◽  
Binding Free Energy ◽  
Uv Spectrophotometry ◽  
Docking Simulations ◽  
Oxidase Enzyme

Objective: The aim of the present study was to examine the inhibiting effects of quercetin contained in Sonchusarvensis leaf extract on the activity of xanthine oxidase, an essential enzyme for uric acid synthesis.Methods: Activity test was conducted in vitro by measuring the activity of xanthine oxidase using UV spectrophotometry and in silico by determining the interaction of quercetin and allopurinol (as comparation drug) with xanthine oxidase enzyme in terms of hydrogen bonds and binding free energy. Docking simulations were performed by Autodock4.2 package.Results: The active fraction, using the solvent n-hexane, ethyl acetate and water, tested the inhibitory activity of the xanthine oxidase enzyme in vitro obtained respectively IC50 of 263.19, 16.20 and 141.80 μg/ml. Isolates with highest activity identified as quercetin. The xanthine oxidase enzyme inhibitory activity insilico by molecular docking showed quercetin has free energy binding ˗7.71 kcal/mol, more negative than that of allopurinol ˗5.63 kcal/mol.Conclusion: This shows the affinity of quercetin stronger than that of allopurinol; so that it can be predicted that quercetin was more potential to inhibit xanthine oxidase enzyme activity. Thus the extract of the S. arvensis leaves containing the active compound quercetin was a potential use as antihyperuricemia.  

scholarly journals In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus

2021 ◽  
Vol 14 (10) ◽  
pp. 1027
Author(s):  
Danielle R. Garcia ◽  
Felipe R. Souza ◽  
Ana P. Guimarães ◽  
Martin Valis ◽  
Zbyšek Pavelek ◽  
...  
Keyword(s):  
Free Energy ◽  
Active Sites ◽  
Free Energy Calculations ◽  
Variola Virus ◽  
Selective Inhibitors ◽  
Thymidylate Kinase ◽  
In Silico Studies ◽  
Docking Calculations ◽  
Poisson Boltzmann ◽  
Dynamics Simulations

Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

scholarly journals Computational Analyses of the AtTPC1 (Arabidopsis Two-Pore Channel 1) Permeation Pathway

2021 ◽  
Vol 22 (19) ◽  
pp. 10345
Author(s):  
Carlos Navarro-Retamal ◽  
Stephan Schott-Verdugo ◽  
Holger Gohlke ◽  
Ingo Dreyer
Keyword(s):  
Free Energy ◽  
Relative Permeability ◽  
In Silico ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Pore Channel ◽  
Luminal Side ◽  
Electrophysiological Studies ◽  
Sv Channels ◽  
Computational Analyses

Two Pore Channels (TPCs) are cation-selective voltage- and ligand-gated ion channels in membranes of intracellular organelles of eukaryotic cells. In plants, the TPC1 subtype forms the slowly activating vacuolar (SV) channel, the most dominant ion channel in the vacuolar membrane. Controversial reports about the permeability properties of plant SV channels fueled speculations about the physiological roles of this channel type. TPC1 is thought to have high Ca2+ permeability, a conclusion derived from relative permeability analyses using the Goldman–Hodgkin–Katz (GHK) equation. Here, we investigated in computational analyses the properties of the permeation pathway of TPC1 from Arabidopsis thaliana. Using the crystal structure of AtTPC1, protein modeling, molecular dynamics (MD) simulations, and free energy calculations, we identified a free energy minimum for Ca2+, but not for K+, at the luminal side next to the selectivity filter. Residues D269 and E637 coordinate in particular Ca2+ as demonstrated in in silico mutagenesis experiments. Such a Ca2+-specific coordination site in the pore explains contradicting data for the relative Ca2+/K+ permeability and strongly suggests that the Ca2+ permeability of SV channels is largely overestimated from relative permeability analyses. This conclusion was further supported by in silico electrophysiological studies showing a remarkable permeation of K+ but not Ca2+ through the open channel.

The inhibitory Effects of Some Artificial Food Colorings on α-amylase and α-glucosidase: In Vitro and In Silico Studies

2021 ◽  
Vol 17 ◽  
Author(s):  
Reguia Mahfoudi ◽  
Amar Djeridane ◽  
Djilali Tahri ◽  
Mohamed Yousfi
Keyword(s):  
In Silico ◽  
Hydrophobic Interactions ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Qsar Study ◽  
Molegro Virtual Docker ◽  
Artificial Food ◽  
In Silico Studies ◽  
Ic50 Values

Background: Inhibition of α-amylase and α-glucosidase is considered as an important therapeutic target to manage type 2 diabetes mellitus (T2DM), reducing postprandial hyperglycemia (PPHG). Objective: The present work explored the antidiabetic activities of five artificial food colorings by α-amylase and α-glucosidase enzyme inhibition in vitro and in Silico. Methods: In this study, inhibition of α-amylase and α-glucosidase were evaluated. Further, the interaction between enzymes (α-amylase and α-glucosidase) and ligands (food colorings) was followed by QSAR and molecular docking studies. Results: The in vitro results obtained show that the blue patent (SIN131) exhibited more potent inhibition with IC50 values of 0.03± 0.01 mM and 0.014±0.001 mM against α-amylase and α-glucosidase inhibition respectively compared to acarbose. The QSAR study found a strong correlation between IC50 values with four molecular descriptors. This linear regression confirms that a strong polarity (Apol) and a low hydrophobia (ALogP) favor the inhibitory effect of these colorings toward both enzymes. Also, a negative role of the number of heavy atoms has been demonstrated in the phenomenon of inhibition of this enzyme. Finally, the descriptor εlumo (electronic affinity) plays a crucial role on the inhibitory power of these dyes toward both enzymes by electron transfer. The virtual screening of the inhibition of α-amylase and α-glucosidase by these colorings, using Molegro Virtual Docker (MVD), allowed us to obtain stable complexes with interaction energies resulting from the place of hydrogen bonds and several hydrophobic interactions. However, the sulfonate groups of these colorings can be the major factors in the inhibition of these enzymes. On the other hand, Rerank Score with the pose are perfectly correlated (R2> 0.76) to the inhibitory activity of these food colorings measured experimentally. Conclusion: The present study suggests that the Blue Patent V (SIN131) effectively act as α-amylase and α-glucosidase inhibitor leading to a reduction in starch hydrolysis and hence eventually to lowered glucose levels.

Dengue Virus Inhibition Targets: A Review and Docking Study

2018 ◽  
Vol 18 (18) ◽  
pp. 1522-1530 ◽  
Author(s):  
Luciana Scotti ◽  
Marcus Tullius Scotti ◽  
Nagendra Sastry Yarla ◽  
Alex France Messias Monteiro ◽  
Jessika de Oliveira Viana ◽  
...  
Keyword(s):  
Dengue Virus ◽  
In Silico ◽  
Hemorrhagic Fever ◽  
Docking Study ◽  
World Population ◽  
Protease Inhibition ◽  
Virus Inhibition ◽  
Severe Manifestation ◽  
Density Analysis ◽  
Ns3 Protease

Dengue like any neglected tropical disease affects a large part of the world population. In this disease, the infection is caused by arboviruses transmitted by the A. aegypti and A. albopictus mosquito, in which its most severe manifestation is known as dengue hemorrhagic fever. The infected person presents symptoms characteristic of such as fever and rash. Among the ways of fighting dengue by bioactives is the inhibition of NS2B-NS3 protease, inhibition of protein E, and inhibition of sclerotization of the vector cuticle. The cuticle is indispensable for the survival of the mosquito that can be compromised through the inhibition of arylalkylamine N-acetyltransferase (aaNAT). In the studies shown, in silico tests were performed as molecular docking, functional density analysis, molecular orbitals energies with the analyses of the interactions between bioactives and the targets studied. However, in addition to discussing the fight against dengue virus infection through different routes, in this paper, some in silico results of 27 analogs of myricetin have been presented, which showed action on the cuticle sclerotization mechanism.

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