(2-Hydroxy-4-methoxy)benzyl Aminoadamantane Conjugates as Probes to Investigate Specificity Determinants in Blocking Influenza M2 S31N and M2 WT Channels with Binding Kinetics and Simulations

2020 ◽  
Author(s):  
Christina Tzitzoglaki ◽  
Kelly McGuire ◽  
Athina Konstantinidi ◽  
Panagiotis Lagarias ◽  
Anja Hoffmann ◽  
...  
Keyword(s):  
Rate Constants ◽  
Influenza A ◽  
Md Simulations ◽  
Proton Channel ◽  
Head Group ◽  
Polar Head Group ◽  
Polar Head ◽  
The Impact ◽  
Low K ◽  
Proton Currents

<p>In an attempt to synthesize potent blockers of the influenza A M2 S31N proton channel with modifications of amantadine, we used MD simulations and MM-PBSA calculations to project binding modes of compounds <b>2-5,</b> which are analogues of <b>1</b>, a dual blocker. Blocking both the S31N mutant and the wild type (WT) M2, <b>1 </b>is composed of amantadine linked to an aryl head group, (4-methoxy-2-hydroxy)-benzyl. Compound <b>6</b>, used as control, has an 3-(thiophenyl)isoxazolyl aryl head group, and selectively blocks M2 S31N (but not WT) in an aryl head group “out” (i.e. N-ward) binding orientation. We then tested <b>1</b>-<b>6</b> as anti-virals in cell culture and for M2 binding efficacy with electrophysiology (EP). The new molecules <b>2-5</b> have a linker between the adamantane and amino group which can be as small as a CMe<sub>2</sub> in rimantadine derivative <b>2</b>, or longer like phenyl in <b>3</b>. Alternatively, we explored the impact of expanding the diameter of adamantane with diamantyl or triamantyl in <b>4 </b>and<b> 5</b>, respectively. Antiviral effects against A/WSN/33 and its M2 WT revertant (M2 N31S) were seen for all six compounds except for <b>5</b> vs. the native (S31N) virus and (as predicted from previous studies) <b>6</b> vs. the WT revertant. Compounds <b>1-5, </b>projected to bind<b> </b>in a polar head group “in” (C-ward) orientation, strongly block<b> </b>proton currents through M2 WT expressed in voltage-clamped oocytes with fast association rate constants (k<sub>on</sub>), and slow dissociation rate constants (k<sub>off</sub>). Surprisingly,<b> 2-5, </b>projected to bind<b> </b>in a polar head group out orientation, do not effectively block M2 S31N-mediated proton currents in EP. The results from MD and MM-PBSA calculations suggested that compounds <b>2</b>-<b>5</b> can be fully effective at blocking the M2 channel when present. The low degree of blocking in M2 S31N is due to their kinetics of binding observed in EP, i.e. two orders of magnitude reduction in k<sub>on </sub>compared to <b>6</b>, and a fast off rate constant similar to that of <b>6</b>,<b> </b>which is consistent with<b> </b>steered-MDsimulations. The low k<sub>on</sub> values can be interpreted from MD simulations, which suggest distortions to V27 cluster of the M2 S31N caused by the longer (even by one methylene) hydrophobic segment from adamantane to aryl head group, appropriate to fit from G34 to V27. The deformations in the N-terminus may be sufficiently energetic for <b>2-5</b> (compared to <b>6</b>)<b> </b>to cause the observed low k<sub>on</sub>. <br></p>

(2-Hydroxy-4-methoxy)benzyl Aminoadamantane Conjugates as Probes to Investigate Specificity Determinants in Blocking Influenza M2 S31N and M2 WT Channels with Binding Kinetics and Simulations

2020 ◽  
Author(s):  
Christina Tzitzoglaki ◽  
Kelly McGuire ◽  
Athina Konstantinidi ◽  
Panagiotis Lagarias ◽  
Anja Hoffmann ◽  
...  
Keyword(s):  
Rate Constants ◽  
Influenza A ◽  
Md Simulations ◽  
Proton Channel ◽  
Head Group ◽  
Polar Head Group ◽  
Polar Head ◽  
The Impact ◽  
Low K ◽  
Proton Currents

<p>In an attempt to synthesize potent blockers of the influenza A M2 S31N proton channel with modifications of amantadine, we used MD simulations and MM-PBSA calculations to project binding modes of compounds <b>2-5,</b> which are analogues of <b>1</b>, a dual blocker. Blocking both the S31N mutant and the wild type (WT) M2, <b>1 </b>is composed of amantadine linked to an aryl head group, (4-methoxy-2-hydroxy)-benzyl. Compound <b>6</b>, used as control, has an 3-(thiophenyl)isoxazolyl aryl head group, and selectively blocks M2 S31N (but not WT) in an aryl head group “out” (i.e. N-ward) binding orientation. We then tested <b>1</b>-<b>6</b> as anti-virals in cell culture and for M2 binding efficacy with electrophysiology (EP). The new molecules <b>2-5</b> have a linker between the adamantane and amino group which can be as small as a CMe<sub>2</sub> in rimantadine derivative <b>2</b>, or longer like phenyl in <b>3</b>. Alternatively, we explored the impact of expanding the diameter of adamantane with diamantyl or triamantyl in <b>4 </b>and<b> 5</b>, respectively. Antiviral effects against A/WSN/33 and its M2 WT revertant (M2 N31S) were seen for all six compounds except for <b>5</b> vs. the native (S31N) virus and (as predicted from previous studies) <b>6</b> vs. the WT revertant. Compounds <b>1-5, </b>projected to bind<b> </b>in a polar head group “in” (C-ward) orientation, strongly block<b> </b>proton currents through M2 WT expressed in voltage-clamped oocytes with fast association rate constants (k<sub>on</sub>), and slow dissociation rate constants (k<sub>off</sub>). Surprisingly,<b> 2-5, </b>projected to bind<b> </b>in a polar head group out orientation, do not effectively block M2 S31N-mediated proton currents in EP. The results from MD and MM-PBSA calculations suggested that compounds <b>2</b>-<b>5</b> can be fully effective at blocking the M2 channel when present. The low degree of blocking in M2 S31N is due to their kinetics of binding observed in EP, i.e. two orders of magnitude reduction in k<sub>on </sub>compared to <b>6</b>, and a fast off rate constant similar to that of <b>6</b>,<b> </b>which is consistent with<b> </b>steered-MDsimulations. The low k<sub>on</sub> values can be interpreted from MD simulations, which suggest distortions to V27 cluster of the M2 S31N caused by the longer (even by one methylene) hydrophobic segment from adamantane to aryl head group, appropriate to fit from G34 to V27. The deformations in the N-terminus may be sufficiently energetic for <b>2-5</b> (compared to <b>6</b>)<b> </b>to cause the observed low k<sub>on</sub>. <br></p>

scholarly journals Computational and experimental evidence to the permeability of withanolides across the normal cell membrane

2019 ◽  
Author(s):  
R. Wadhwa ◽  
N. S. Yadav ◽  
S. P Katiyar ◽  
T. Yaguchi ◽  
C. Lee ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Chemical Properties ◽  
Md Simulations ◽  
Computational Method ◽  
Withaferin A ◽  
Head Group ◽  
Polar Head Group ◽  
Drug Molecules ◽  
Natural Drugs ◽  
The Impact

AbstractPoor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in the clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs - withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that withaferin-A, but not withanone, could proficiently transverse through the model membrane. The free energy profiles obtained were in accordance with the physico-chemical properties of the investigated drug molecules. It was observed that the polar head group of the bilayer exhibits high resistance for the passage of withanone as compared to withaferin-A, while the interior of the membrane behaves similarly for both withanolides. The solvation analysis revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force. The impact of the favorable interaction of terminal oxygen (O5) of withaferin-A with the phosphate of the membrane led to its smooth passage across the bilayer. The computational predictions were validated by raising and recruiting unique antibodies that react to withaferin-A and withanone. Further, the time-lapsed analyses of control and treated human normal and cancer cells, demonstrated proficient permeation of withaferin-A, but not withanone, through normal cells. These data strongly validated our computational method for predicting permeability and hence bioavailability of candidate compounds in the drug development process.Statement of significanceWhat determines the bioavailability of a drug? Does the ability to cross cell membrane determine this? A combined simulation/experimental study of the permeability of two natural drugs - withanolides (Wi-A and Wi-N) across the cell membrane was conducted. In the computational portion of the study, steered MD simulations were performed to investigate the propensity of the two molecules to permeate across the cell. It is found that Wi-A proceeds relatively simply across the cell compared to Wi-N. This trend was found to be consistent with experiment. This work is an important step towards understanding the molecular basis of permeability of natural drug molecules.

The effect of polar head group of dodecyl surfactants on the growth of wheat and cucumber

Chemosphere ◽  
2020 ◽  
Vol 254 ◽  
pp. 126918
Author(s):  
Aleksandar Tot ◽  
Ivana Maksimović ◽  
Marina Putnik-Delić ◽  
Milena Daničić ◽  
Slobodan Gadžurić ◽  
...  
Keyword(s):  
Head Group ◽  
Polar Head Group ◽  
Polar Head

Glycosylinositol phosphoceramide-specific phospholipase D activity catalyzes transphosphatidylation

2019 ◽  
Vol 166 (5) ◽  
pp. 441-448 ◽  
Author(s):  
Rumana Yesmin Hasi ◽  
Makoto Miyagi ◽  
Katsuya Morito ◽  
Toshiki Ishikawa ◽  
Maki Kawai-Yamada ◽  
...  
Keyword(s):  
Chain Length ◽  
Phospholipase D ◽  
Secondary Alcohol ◽  
Primary Alcohol ◽  
Tertiary Alcohol ◽  
Head Group ◽  
Polar Head Group ◽  
Polar Head ◽  
A Chain ◽  
Sugar Chains

Abstract Glycosylinositol phosphoceramide (GIPC) is the most abundant sphingolipid in plants and fungi. Recently, we detected GIPC-specific phospholipase D (GIPC-PLD) activity in plants. Here, we found that GIPC-PLD activity in young cabbage leaves catalyzes transphosphatidylation. The available alcohol for this reaction is a primary alcohol with a chain length below C4. Neither secondary alcohol, tertiary alcohol, choline, serine nor glycerol serves as an acceptor for transphosphatidylation of GIPC-PLD. We also found that cabbage GIPC-PLD prefers GIPC containing two sugars. Neither inositol phosphoceramide, mannosylinositol phosphoceramide nor GIPC with three sugar chains served as substrate. GIPC-PLD will become a useful catalyst for modification of polar head group of sphingophospholipid.

Changes in phospholipid polar head group turnover in SV40-transformed hamster fibroblasts

FEBS Letters ◽  
1982 ◽  
Vol 139 (2) ◽  
pp. 217-220 ◽  
Author(s):  
Cécile Maziére ◽  
Jean-Claude Maziére ◽  
Liliana Mora ◽  
Jacques Polonovski
Keyword(s):  
Head Group ◽  
Polar Head Group ◽  
Polar Head

scholarly journals Biosynthesis of Ether-Type Polar Lipids in Archaea and Evolutionary Considerations

2007 ◽  
Vol 71 (1) ◽  
pp. 97-120 ◽  
Author(s):  
Yosuke Koga ◽  
Hiroyuki Morii
Keyword(s):  
Mevalonate Pathway ◽  
Polar Lipids ◽  
In Vivo Studies ◽  
Head Group ◽  
Polar Head Group ◽  
Phospholipid Synthesis ◽  
Polar Head ◽  
Head Groups

SUMMARY This review deals with the in vitro biosynthesis of the characteristics of polar lipids in archaea along with preceding in vivo studies. Isoprenoid chains are synthesized through the classical mevalonate pathway, as in eucarya, with minor modifications in some archaeal species. Most enzymes involved in the pathway have been identified enzymatically and/or genomically. Three of the relevant enzymes are found in enzyme families different from the known enzymes. The order of reactions in the phospholipid synthesis pathway (glycerophosphate backbone formation, linking of glycerophosphate with two radyl chains, activation by CDP, and attachment of common polar head groups) is analogous to that of bacteria. sn-Glycerol-1-phosphate dehydrogenase is responsible for the formation of the sn-glycerol-1-phosphate backbone of phospholipids in all archaea. After the formation of two ether bonds, CDP-archaeol acts as a common precursor of various archaeal phospholipid syntheses. Various phospholipid-synthesizing enzymes from archaea and bacteria belong to the same large CDP-alcohol phosphatidyltransferase family. In short, the first halves of the phospholipid synthesis pathways play a role in synthesis of the characteristic structures of archaeal and bacterial phospholipids, respectively. In the second halves of the pathways, the polar head group-attaching reactions and enzymes are homologous in both domains. These are regarded as revealing the hybrid nature of phospholipid biosynthesis. Precells proposed by Wächtershäuser are differentiated into archaea and bacteria by spontaneous segregation of enantiomeric phospholipid membranes (with sn-glycerol-1-phosphate and sn-glycerol-3-phosphate backbones) and the fusion and fission of precells. Considering the nature of the phospholipid synthesis pathways, we here propose that common phospholipid polar head groups were present in precells before the differentiation into archaea and bacteria.

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