Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Natural volatiles preventing mosquito biting: an integrated screening platform for accelerated discovery of ORco antagonists
Δημιουργός/Συγγραφέας:	Kythreoti, Georgia Thireou, Trias Karoussiotis, Christos Georgoussi, Zafiroula Liggri, Panagiota G V Papachristos, Dimitrios P Michaelakis, Antonios Karras, Vasileios [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E. Schulz, Stefan Iatrou, Kostas
Ημερομηνία:	2024-10-28
Γλώσσα:	Αγγλικά
ISSN:	00219258
DOI:	10.1016/j.jbc.2024.107939
Άλλο:	39476965
Περίληψη:	Insect olfactory receptors are heteromeric ligand-gated cation channels composed of an obligatory receptor subunit, ORco, and one of many variable subunits, ORx, in as yet undefined molar ratios. When expressed alone ex vivo, ORco forms homotetrameric channels gated by ORco-specific ligands acting as channel agonists. Using an insect cell-based system as a functional platform for expressing mosquito odorant receptors ex vivo, we identified small molecules of natural origin acting as specific ORco channel antagonists, orthosteric or allosteric relative to a postulated ORco agonist binding site, which cause severe inhibition of olfactory function in mosquitoes. In the present communication, we have compiled common structural features of such orthosteric antagonists and developed a ligand-based pharmacophore whose properties are deemed necessary for binding to the agonist binding site and causing inhibition of ORco's biological function. In silico screening of an available collection of natural volatile compounds with the pharmacophore resulted in identification of several ORco antagonist hits. Cell-based functional screening of the same compound collection resulted in the identification of several compounds acting as orthosteric and allosteric antagonists of ORco channel function ex vivo and inducing anosmic behaviors to Aedes albopictus mosquitoes in vivo. Comparison of the in silico screening results with those of the functional assays revealed that the pharmacophore predicted correctly 7 out of the 8 confirmed orthosteric antagonists and none of the allosteric ones. Because the pharmacophore screen produced additional hits that did not cause inhibition of the ORco channel function, we also generated a Support Vector Machine (SVM) model based on two descriptors of all pharmacophore hits. Training of the SVM on the ex vivo validated compound collection resulted in the selection of the confirmed orthosteric antagonists with a very low cross-validation out-of-sample misclassification rate. Employment of the combined pharmacophore-SVM platform for in silico screening of a larger collection of olfaction-relevant volatiles produced several new hits. Functional validation of randomly selected hits and rejected compounds from this screen confirmed the power of this virtual screening platform as a convenient tool for accelerating the pace of discovery of novel vector control agents. To the best of our knowledge, this study is the first one that combines a pharmacophore with a SVM model for identification of AgamORco antagonists and specifically orthosteric ones.
Τίτλος πηγής δημοσίευσης:	The Journal of biological chemistry
Θεματική Κατηγορία:	[EL] Βιοχημεία[EN] Biochemistry [EL] Δομική Βιολογία[EN] Structural Biology [EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry
Λέξεις-Κλειδιά:	ORco antagonists pharmacophore modeling olfaction
EU Grant:	1st Call for H.F.R.I. Research Projects to support Faculty Members & Researchers and the Procurement of High-and the procurement of high-cost research equipment grant
EU Grant identifier:	HFRI-FM17-637
Κάτοχος πνευματικών δικαιωμάτων:	© 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1016/j.jbc.2024.107939
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο