Structural features and binding free energies for non-covalent inhibitors interacting with immunoproteasome by molecular modeling and dynamics simulations

2012 ◽  
Vol 131 (4) ◽  
Author(s):  
Beilei Lei ◽  
Hamza Adel ◽  
Chang-Guo Zhan
Keyword(s):  
Molecular Modeling ◽  
Structural Features ◽  
Free Energies ◽  
Covalent Inhibitors ◽  
Dynamics Simulations ◽  
Binding Free Energies

scholarly journals Novel Harmicines with Improved Potency against Plasmodium

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4376
Author(s):  
Marina Marinović ◽  
Ivana Perković ◽  
Diana Fontinha ◽  
Miguel Prudêncio ◽  
Jana Held ◽  
...  
Keyword(s):  
Carcinoma Cell ◽  
Free Energies ◽  
Erythrocytic Stage ◽  
Cinnamic Acid Derivatives ◽  
Atp Binding Site ◽  
Synthetic Procedure ◽  
Hepatocellular Carcinoma Cell Line ◽  
Dynamics Simulations ◽  
Liver Hepatocellular Carcinoma ◽  
Binding Free Energies

Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a–f and O-harmicines 6a–h were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of P. falciparum, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of P. berghei. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of PfHsp90, while the calculated binding free energies confirmed higher activity of N-harmicines 5 over their O-substituted analogues 6. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.

Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

2014 ◽  
Vol 92 (9) ◽  
pp. 821-830 ◽  
Author(s):  
Zhi-Guang Zhou ◽  
Qi-Zheng Yao ◽  
Dong Lei ◽  
Qing-Qing Zhang ◽  
Ji Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Biological Activities ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Binding Free Energies

Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.

scholarly journals In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-Like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6593
Author(s):  
Mohamed S. Alesawy ◽  
Eslam B. Elkaeed ◽  
Aisha A. Alsfouk ◽  
Ahmed M. Metwaly ◽  
Ibrahim. H. Eissa
Keyword(s):  
Structural Features ◽  
Docking Studies ◽  
Proteolytic Processing ◽  
Binding Modes ◽  
Free Energies ◽  
Essential Enzyme ◽  
Potential Inhibitors ◽  
Molecular Electrostatic Potential Maps ◽  
Better Than ◽  
Binding Free Energies

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).

scholarly journals Aflatoxin B1–Formamidopyrimidine DNA Adducts: Relationships between Structures, Free Energies, and Melting Temperatures

Molecules ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 150 ◽  
Author(s):  
Martin Klvana ◽  
Urban Bren
Keyword(s):  
Aflatoxin B1 ◽  
Structural Features ◽  
Free Energy Calculations ◽  
Dna Duplexes ◽  
Free Energies ◽  
Thermal Stabilities ◽  
Linear Interaction ◽  
Melting Temperatures ◽  
Explicit Solvent ◽  
Dynamics Simulations

Thermal stabilities of DNA duplexes containing Gua (g), α- (a) or β-anomer of formamidopyrimidine-N7-9-hydroxy-aflatoxin B1 (b) differ markedly (Tm: a < g < b ), but the underlying molecular origin of this experimentally observed phenomenon is yet to be identified and determined. Here, by employing explicit-solvent molecular dynamics simulations coupled with free-energy calculations using a combined linear-interaction-energy/linear-response-approximation approach, we explain the quantitative differences in T m in terms of three structural features (bulkiness, order, and compactness) and three energetical contributions (non-polar, electrostatic, and preorganized-electrostatic), and thus advance the current understanding of the relationships between structures, free energies, and thermal stabilities of DNA double helices.

Virtual Screening-Based Discovery of Potent Hypoglycemic Agents: In Silico, Chemical Synthesis and Biological Study

2019 ◽  
Vol 15 ◽  
Author(s):  
Mohammed A. Khedr ◽  
Omar M. M. Mohafez ◽  
Ibrahim A. Al-Haider
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Hypoglycemic Agents ◽  
Type Ii ◽  
Free Energies ◽  
Diabetes Mellitus Type Ii ◽  
Dynamics Simulations ◽  
Binding Free Energies

Background: Dipeptidyl peptidase IV has been reported to be an important target for the development and discovery of new therapies for diabetes mellitus type II. Objective: The main aim of this study is to discover chemical entities that target the inhibition of DPP IV and feature potent hypoglycemic action. Methods: A structure-based virtual screening was applied to discover new hypoglycemic agents. Molecular docking was performed to compute the binding free energies. Molecular dynamics simulations was done to evaluate the binding stability of resulted hits. Results: Seven small non-peptide potential inhibitors of Dipeptidyl peptidase IV with 3-imino-4-(4-substituted phenyl)-1, 2, 5-thiadiazolidine-1,1-dioxide scaffold that were discovered. The binding free energies ranged from -24.50 to -36.06 kJ/mol. Molecular dynamics simulations revealed high stability of all protein-ligand complexes with low root mean square deviation over 10 ns simulation time. The tested compounds expressed a significant reduction in blood glucose level up to 90% with excellent oral glucose tolerance test after 120 minutes of injection in a diabetes mellitus type II animal model. A promising release of insulin was observed with a potential hypoglycemic activity for all compounds. Conclusion: The virtual screening was successful to discover potent hypoglycemic agents with drug-like properties that may need more consideration for future studies and development.

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