scholarly journals Theoretical Study of Sequence Selectivity and Preferred Binding Mode of Psoralen with DNA

2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Patricia Saenz-Méndez ◽  
Rita C. Guedes ◽  
Daniel J. V. A. dos Santos ◽  
Leif A. Eriksson
Keyword(s):  
Molecular Dynamics ◽  
Theoretical Study ◽  
Binding Mode ◽  
Minor Groove Binding ◽  
Binding Modes ◽  
Groove Binding ◽  
Base Pairs ◽  
Sequence Selectivity ◽  
Molecular Dynamics Methods ◽  
Low Efficiency

Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (AT)n sequences.

scholarly journals Mechanism of Selective Inhibition of Yohimbine and Its Derivatives in Adrenoceptorα2 Subtypes

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Liu Hai-Bo ◽  
Peng Yong ◽  
Huang Lu-qi ◽  
Xu Jun ◽  
Xiao Pei-Gen
Keyword(s):  
Molecular Dynamics ◽  
Selective Inhibition ◽  
Binding Mode ◽  
Mode Analysis ◽  
Inhibiting Activity ◽  
Binding Modes ◽  
Molecular Dynamics Methods ◽  
Subtype A ◽  
Key Residues ◽  
Homology Models

Some natural alkaloids from medicinal plants, such as yohimbine and its derivatives, have been reported with adrenoceptor (AR)α2 subtypes inhibiting activity. In trying to address the possible mechanism of the action, a set of homology models of ARα2 was built based on MOE. After that, docking and molecular dynamics methods were used to investigate the binding modes of yohimbine and its 2 derivatives in the active pocket of adrenoceptorα2 subtype A, B, and C. The key interactions between the 3 ligands and the 3 receptors were mapped. Binding mode analysis presents a strong identity in the key residues in each subtype. Only a few differences play the key role in modulating selectivity of yohimbine and its derivatives. These results can guide the design of new selective ARα2 inhibitors.

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

scholarly journals Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

2021 ◽  
Vol 14 (7) ◽  
pp. 685
Author(s):  
Sandra Amanda Kozieł ◽  
Monika Katarzyna Lesiów ◽  
Daria Wojtala ◽  
Edyta Dyguda-Kazimierowicz ◽  
Dariusz Bieńko ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Serum Proteins ◽  
Docking Study ◽  
Minor Groove ◽  
Docking Studies ◽  
Minor Groove Binding ◽  
Binding Modes ◽  
Groove Binding ◽  
Molecular Docking Study ◽  
Threading Intercalation

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

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.

Fragment Pose Prediction Using Non-Equilibrium Candidate Monte Carlo and Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Nathan M. Lim ◽  
Meghan Osato ◽  
Gregory L. Warren ◽  
David L. Mobley
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Monte Carlo ◽  
Ligand Binding ◽  
Md Simulations ◽  
Binding Mode ◽  
Protein Crystal ◽  
Pose Prediction ◽  
Binding Modes ◽  
Non Equilibrium

<div>Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and how molecules bind, chemists can begin to build ideas on how to design improvements to increase binding affinities. In this retrospective study, we compare how computational approaches like docking, molecular dynamics (MD) simulations, and a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting binding modes for a set of 12 fragment-like molecules which bind to soluble epoxide hydrolase. We evaluate each method's effectiveness in identifying the dominant binding mode and finding any additional binding modes (if any). Then, we compare our predicted binding modes to experimentally obtained X-ray crystal structures.</div><div>We dock each of the 12 small molecules into the apo-protein crystal structure and then run simulations up to 1 microsecond each. Small and fragment-like molecules likely have smaller energy barriers separating different binding modes by virtue of relatively fewer and weaker interactions relative to drug-like molecules, and thus likely undergo more rapid binding mode transitions. We expect, thus, to see more rapid transitions betweeen binding modes in our study. </div><div><br></div><div>Following this, we build Markov State Models (MSM) to define our stable ligand binding modes. We investigate if adequate sampling of ligand binding modes and transitions between them can occur at the microsecond timescale using traditional MD or a hybrid NCMC+MD simulation approach. Our findings suggest that even with small fragment-like molecules, we fail to sample all the crystallographic binding modes using microsecond MD simulations, but using NCMC+MD we have better success in sampling the crystal structure while obtaining the correct populations.</div>

Primary photoprocesses in cationic 5,10,15,20-meso-tetrakis(4-N-methylpyridiniumyl)porphyrin and its transition metal complexes bound with nucleic acids

2003 ◽  
Vol 07 (11) ◽  
pp. 766-774 ◽  
Author(s):  
Vladimir S. Chirvony
Keyword(s):  
Excited States ◽  
Transition Metal Complexes ◽  
Photophysical Properties ◽  
Binding Mode ◽  
Axial Ligand ◽  
Guanosine Monophosphate ◽  
Groove Binding ◽  
Base Pairs ◽  
Excited Complex ◽  
Groove Binding Mode

Photophysical properties of meso-tetrakis(4-N-methylpyridiniumyl)porphyrin ( TMpyP 4) and its metallocomplexes M (II) TMpy P4 ( M = Zn , Cu , Ni , Co ) bound to natural DNA and synthetic poly-, oligo- and mononucleotides are considered with a primary emphasis placed upon intermolecular interaction of the photoexcited porphyrins with the nearest environment. Quenching of the fluorescent S 1 (but not triplet T 1) state due to guanine to porphyrin electron transfer is observed for TMpyP 4 intercalated between GC base pairs of the double-strand helixes, whereas in the case of TMpyP 4 complexed with guanosine monophosphate (GMP) both S 1 and T 1 states of the porphyrin are quenched. Furthermore, a dependence of the efficiency of TMpyP 4 triplet state quenching by the dissolved molecular oxygen from air on the porphyrin localization enables one to readily distinguish porphyrin groove binding mode from intercalation. Excited states of the TMpyP 4 complexes with transition metals, in spite of their very short lifetimes, also interact with nucleic acid components by means of an axial ligand binding/release to/from the metal. A possible structure of the five-coordinate excited complex (“exciplex”) formed in case of CuTMpyP 4 groove binding to some single- and double-strand polynucleotides is discussed.

The DNA-Porphyrin Interactions Studied by Vibrational and Electronic Circular Dichroism Spectroscopy

2005 ◽  
Vol 70 (11) ◽  
pp. 1799-1810 ◽  
Author(s):  
Jakub Nový ◽  
Marie Urbanová ◽  
Karel Volka
Keyword(s):  
Circular Dichroism ◽  
Conformational Changes ◽  
Binding Mode ◽  
Minor Groove ◽  
Binding Modes ◽  
Base Pairs ◽  
Electronic Circular Dichroism ◽  
Axial Ligands ◽  
Phosphate Backbone ◽  
Circular Dichroïsm

The interactions of three different porphyrins, without axial ligands - 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin-Cu(II) tetrachloride (Cu(II)TMPyP), with axial ligands - 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin-Fe(III) pentachloride (Fe(III)TMPyP), and with bulky meso substituents - 5,10,15,20-tetrakis(N,N,N-trimethylanilinium-4-yl)-porphyrin tetrachloride (TMAP), with calf thymus DNA were studied by combination of vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopy, and by IR and UV-VIS absorption spectroscopy. It has been shown that Cu(II)TMPyP prefers the intercalative binding mode with DNA in the GC-rich regions and the intercalative sites are saturated at the c(DNA)/c(Cu(II)TMPyP) ratio ~3:1, where c(DNA) and c(Cu(II)TMPyP) are total molar concentrations of nucleic acid in base pairs and porphyrin, respectively. Fe(III)TMPyP does not intercalate between the GC base pairs but binds to DNA in the minor groove. At higher c(DNA)/c(TMAP) ratios, TMAP interacts with DNA in the minor groove, but at lower ratios in the major groove and by the external binding mode accompanied by self-stacking of porphyrins along the phosphate backbone. VCD spectroscopy reliably discriminates the binding modes and specifies the conformational changes of the DNA matrices. It has been also shown that VCD spectroscopy is an effective tool for the conformational studies of DNA-porphyrin complexes. New spectroscopic "markers" in VCD spectra have been found for the specific DNA-porphyrin interactions.

scholarly journals Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing

2017 ◽  
Author(s):  
Hovakim Grabski ◽  
Lernik Hunanyan ◽  
Susanna Tiratsuyan ◽  
Hrachik Vardapetyan
Keyword(s):  
Molecular Dynamics ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Principal Component ◽  
Transcriptional Regulator ◽  
Binding Mode ◽  
World Health ◽  
Hydroxyl Group ◽  
Binding Modes

ABSTRACTBackgroundPseudomonas aeruginosais one of the most dangerous superbugs in the list of bacteria for which new antibiotics are urgently needed, which was published by World Health Organization.P. aeruginosais an antibiotic-resistant opportunistic human pathogen. It affects patients with AIDS, cystic fibrosis, cancer, burn victims and people with prosthetics and implants.P. aeruginosaalso forms biofilms. Biofilms increase resistance to antibiotics and host immune responses. Because of biofilms, current therapies are not effective. It is important to find new antibacterial treatment strategies againstP. aeruginosa. Biofilm formation is regulated through a system called quorum sensing. Thus disrupting this system is considered a promising strategy to combat bacterial pathogenicity. It is known that quercetin inhibitsPseudomonas aeruginosabiofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with quercetin.ResultsWe used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques for the study of the interaction of the LasR protein ofP. aeruginosawith quercetin. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of quercetin with LasR. We show that quercetin has two binding modes. One binding mode is the interaction with ligand binding domain, this interaction is not competitive and it has also been shown experimentally. The second binding mode is the interaction with the bridge, it involves conservative amino acid interactions from LBD, SLR, and DBD and it is also not competitive. Experimental studies show hydroxyl group of ring A is necessary for inhibitory activity, in our model the hydroxyl group interacts with Leu177 during the second binding mode. This could explain the molecular mechanism of how quercetin inhibits LasR protein.ConclusionsThis study may offer insights on how quercetin inhibits quorum sensing circuitry by interacting with transcriptional regulator LasR. The capability of having two binding modes may explain why quercetin is effective at inhibiting biofilm formation and virulence gene expression.List of abbreviationsPDBProtein data bankMDMolecular DynamicsPCAPrincipal Component AnalysisPCPrincipal ComponentSLRShort Linker RegionBLASTBasic local alignment search toolDBIDavid-Bouldin IndexpsFpseudo-F statistic

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