17673
2018
eng
5281-5290
5
3
article
1
2019-02-15
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In silico designed Axl receptor blocking drug candidates against Zika virus infection
After a large outbreak in Brazil, novel drugs against Zika virus became extremely necessary. Evaluation of virus-based pharmacological strategies concerning essential host factors brought us to the idea that targeting the Axl receptor by blocking its dimerization function could be critical for virus entry. Starting from experimentally validated compounds, such as RU-301, RU-302, warfarin, and R428, we identified a novel compound 2′ (R428 derivative) to be the most potent for this task amongst a number of alternative compounds and leads. The improved affinity of compound 2′ was confirmed by molecular docking as well as molecular dynamics simulation techniques using implicit solvation models. The current study summarizes a new possibility for inhibition of the Axl function as a potential target for future antiviral therapies.
ACS Omega
10.1021/acsomega.8b00223
urn:nbn:de:bvb:20-opus-176739
ACS Omega 2018, 3(5), 5281-5290. DOI: 10.1021/acsomega.8b00223
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Edita Sarukhanyan
Sergey Shityakov
Thomas Dandekar
eng
uncontrolled
free energy
eng
uncontrolled
molecular docking
eng
uncontrolled
molecular dynamics
eng
uncontrolled
simulation
eng
uncontrolled
pharmacology
eng
uncontrolled
proteins
eng
uncontrolled
structure-activity relationship
eng
uncontrolled
viruses
eng
uncontrolled
Zika virus
Pharmakologie, Therapeutik
open_access
Klinik und Poliklinik für Anästhesiologie (ab 2004)
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17673/Sarukhanyan_ACS_Omega.pdf
13459
2012
eng
e1003023
11
8
article
1
2016-06-09
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Trypanosome Motion Represents an Adaptation to the Crowded Environment of the Vertebrate Bloodstream
Blood is a remarkable habitat: it is highly viscous, contains a dense packaging of cells and perpetually flows at velocities varying over three orders of magnitude. Only few pathogens endure the harsh physical conditions within the vertebrate bloodstream and prosper despite being constantly attacked by host antibodies. African trypanosomes are strictly extracellular blood parasites, which evade the immune response through a system of antigenic variation and incessant motility. How the flagellates actually swim in blood remains to be elucidated. Here, we show that the mode and dynamics of trypanosome locomotion are a trait of life within a crowded environment. Using high-speed fluorescence microscopy and ordered micro-pillar arrays we show that the parasites mode of motility is adapted to the density of cells in blood. Trypanosomes are pulled forward by the planar beat of the single flagellum. Hydrodynamic flow across the asymmetrically shaped cell body translates into its rotational movement. Importantly, the presence of particles with the shape, size and spacing of blood cells is required and sufficient for trypanosomes to reach maximum forward velocity. If the density of obstacles, however, is further increased to resemble collagen networks or tissue spaces, the parasites reverse their flagellar beat and consequently swim backwards, in this way avoiding getting trapped. In the absence of obstacles, this flagellar beat reversal occurs randomly resulting in irregular waveforms and apparent cell tumbling. Thus, the swimming behavior of trypanosomes is a surprising example of micro-adaptation to life at low Reynolds numbers. For a precise physical interpretation, we compare our high-resolution microscopic data to results from a simulation technique that combines the method of multi-particle collision dynamics with a triangulated surface model. The simulation produces a rotating cell body and a helical swimming path, providing a functioning simulation method for a microorganism with a complex swimming strategy.
PLoS Pathogens
10.1371/journal.ppat.1003023
urn:nbn:de:bvb:20-opus-134595
PLoS Pathogens 8(11): e1003023. doi:10.1371/journal.ppat.1003023
Niko Heddergott
Timothy Krüger
Sujin B. Babu
Ai Wei
Erik Stellamanns
Sravanti Uppaluri
Thomas Pfohl
Holger Stark
Markus Engstler
eng
uncontrolled
simulation
eng
uncontrolled
multiparticle collision dynamics
eng
uncontrolled
propulsion
eng
uncontrolled
viscosity
eng
uncontrolled
flagellar
eng
uncontrolled
motility
eng
uncontrolled
solvent
eng
uncontrolled
model
eng
uncontrolled
hydrodynamics
eng
uncontrolled
spiroplasma
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg