TY  - JOUR
A1  - Sarukhanyan, Edita
A1  - Shityakov, Sergey
A1  - Dandekar, Thomas
T1  - Rational drug design of Axl tyrosine kinase type I inhibitors as promising candidates against cancer
JF  - Frontiers in Chemistry
N2  - The high level of Axl tyrosine kinase expression in various cancer cell lines makes it an attractive target for the development of anti-cancer drugs. In this study, we carried out several sets of in silico screening for the ATP-competitive Axl kinase inhibitors based on different molecular docking protocols. The best drug-like candidates were identified, after parental structure modifications, by their highest affinity to the target protein. We found that our newly designed compound R5, a derivative of the R428 patented analog, is the most promising inhibitor of the Axl kinase according to the three molecular docking algorithms applied in the study. The molecular docking results are in agreement with the molecular dynamics simulations using the MM-PBSA/GBSA implicit solvation models, which confirm the high affinity of R5 toward the protein receptor. Additionally, the selectivity test against other kinases also reveals a high affinity of R5 toward ABL1 and Tyro3 kinases, emphasizing its promising potential for the treatment of malignant tumors.
KW  - Axl tyrosine kinase
KW  - anti-cancer drug-like molecules
KW  - rational drug design
KW  - molecular docking
KW  - molecular dynamics
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199505
SN  - 2296-2646
VL  - 7
IS  - 920
ER  - 
TY  - JOUR
A1  - Sarukhanyan, Edita
A1  - Shityakov, Sergey
A1  - Dandekar, Thomas
T1  - In silico designed Axl receptor blocking drug candidates against Zika virus infection
JF  - ACS Omega
N2  - 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.
KW  - free energy
KW  - molecular docking
KW  - molecular dynamics
KW  - simulation
KW  - pharmacology
KW  - proteins
KW  - structure-activity relationship
KW  - viruses
KW  - Zika virus
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176739
VL  - 3
IS  - 5
ER  - 
TY  - JOUR
A1  - Shityakov, Sergey
A1  - Salvador, Ellaine
A1  - Pastorin, Giorgia
A1  - Förster, Carola
T1  - Blood-brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate
JF  - International Journal of Nanomedicine
N2  - In this study, the ability of a multiwalled carbon nanotube functionalized with fluorescein isothiocyanate (MWCNT-FITC) was assessed as a prospective central nervous system-targeting drug delivery system to permeate the blood-brain barrier. The results indicated that the MWCNT-FITC conjugate is able to penetrate microvascular cerebral endothelial monolayers; its concentrations in the Transwell® system were fully equilibrated after 48 hours. Cell viability test, together with phase-contrast and fluorescence microscopies, did not detect any signs of MWCNT-FITC toxicity on the cerebral endothelial cells. These microscopic techniques also revealed presumably the intracellular localization of fluorescent MWCNT-FITCs apart from their massive nonfluorescent accumulation on the cellular surface due to nanotube lipophilic properties. In addition, the 1,000 ps molecular dynamics simulation in vacuo discovered the phenomenon of carbon nanotube aggregation driven by van der Waals forces via MWCN-TFITC rapid dissociation as an intermediate phase.
KW  - endothelial cells
KW  - cytotoxicity
KW  - blood-brain barrier
KW  - fluorescein isothiocyanate
KW  - aggregation
KW  - molecular dynamics
KW  - fluorescence microscopy
KW  - Transwell® system
KW  - multiwalled carbon nanotube
KW  - mice
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149233
VL  - 10
ER  -