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Title
Japanese:Modeling the SDF-1/CXCR4 protein using advanced artificial intelligence and antagonist screening for Japanese anchovy 
English:Modeling the SDF-1/CXCR4 protein using advanced artificial intelligence and antagonist screening for Japanese anchovy 
Author
Japanese: Issei Yahiro, Kyle Dominic Eguid Barnuevo, Oga Sato, Sipra Mohapatra, Atsushi Toyoda, 伊藤武彦, Kaoru Ohno, Michiya Matsuyama, Tapas Chakraborty, Kohei Ohta.  
English: Issei Yahiro, Kyle Dominic Eguid Barnuevo, Oga Sato, Sipra Mohapatra, Atsushi Toyoda, Takehiko Itoh, Kaoru Ohno, Michiya Matsuyama, Tapas Chakraborty, Kohei Ohta.  
Language English 
Journal/Book name
Japanese:Frontiers in Physiology 
English:Frontiers in Physiology 
Volume, Number, Page        
Published date Feb. 2, 2024 
Publisher
Japanese: 
English: 
Conference name
Japanese: 
English: 
Conference site
Japanese: 
English: 
Official URL http://dx.doi.org/10.3389/fphys.2024.1349119
 
DOI https://doi.org/10.3389/fphys.2024.1349119
Abstract <jats:p>SDF-1/CXCR4 chemokine signaling are indispensable for cell migration, especially the Primordial Germ Cell (PGC) migration towards the gonadal ridge during early development. We earlier found that this signaling is largely conserved in the Japanese anchovy (<jats:italic>Engraulis japonicus</jats:italic>, EJ), and a mere treatment of CXCR4 antagonist, AMD3100, leads to germ cell depletion and thereafter gonad sterilization. However, the effect of AMD3100 was limited. So, in this research, we scouted for CXCR4 antagonist with higher potency by employing advanced artificial intelligence deep learning-based computer simulations. Three potential candidates, AMD3465, WZ811, and LY2510924, were selected and <jats:italic>in vivo</jats:italic> validation was conducted using Japanese anchovy embryos. We found that seven transmembrane motif of EJ CXCR4a and EJ CXCR4b were extremely similar with human homolog while the CXCR4 chemokine receptor N terminal (PF12109, essential for SDF-1 binding) was missing in EJ CXCR4b. 3D protein analysis and cavity search predicted the cavity in EJ CXCR4a to be five times larger (6,307 Å³) than that in EJ CXCR4b (1,241 Å³). Docking analysis demonstrated lower binding energy of AMD3100 and AMD3465 to EJ CXCR4a (Vina score −9.6) and EJ CXCR4b (Vina score −8.8), respectively. Furthermore, we observed significant PGC mismigration in microinjected AMD3465 treated groups at 10, 100 and 1 × 10<jats:sup>5</jats:sup> nM concentration in 48 h post fertilized embryos. The other three antagonists showed various degrees of PGC dispersion, but no significant effect compared to their solvent control at tested concentrations was observed. Cumulatively, our results suggests that AMD3645 might be a better candidate for abnormal PGC migration in Japanese anchovy and warrants further investigation.</jats:p>

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