Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Docking, MD Simulations, and DFT Calculations: Assessing W254's Function and Sartan Binding in Furin
Δημιουργός/Συγγραφέας:	Georgiou, Nikitas [EL] Μαυρομούστακος, Θωμάς[EN] Mavromoustakos, Thomas [EL] Τζέλη, Δήμητρα[EN] Tzeli, Demeter
Ημερομηνία:	2024-07-30
Γλώσσα:	Αγγλικά
ISSN:	1467-3045
DOI:	10.3390/cimb46080486
Άλλο:	39194703
Περίληψη:	Furins are serine endoproteases that are involved in many biological processes, where they play important roles in normal metabolism, in the activation of various pathogens, while they are a target for therapeutic intervention. Dichlorophenyl-pyridine "BOS" compounds are well known drugs that are used as inhibitors of human furin by an induced-fit mechanism, in which tryptophan W254 in the furin catalytic cleft acts as a molecular transition energy gate. The binding of "BOS" drug into the active center of furin has been computationally studied using the density functional theory (DFT) and ONIOM multiscaling methodologies. The binding enthalpies of the W254 with the furin-BOS is -32.8 kcal/mol ("open") and -18.8 kcal/mol ("closed"), while the calculated torsion barrier was found at 30 kcal/mol. It is significantly smaller than the value of previous MD calculations due to the relaxation of the environment, i.e., nearby groups of the W254, leading to the reduction of the energy demands. The significant lower barrier explains the experimental finding that the dihedral barrier of W254 is overcome. Furthermore, sartans were studied to evaluate their potential as furin inhibitors. Sartans are AT1 antagonists, and they effectively inhibit the hypertensive effects induced by the peptide hormone Angiotensin II. Here, they have been docked into the cavity to evaluate their effect on the BOS ligand via docking and molecular dynamics simulations. A consistent binding of sartans within the cavity during the simulation was found, suggesting that they could act as furin inhibitors. Finally, sartans interact with the same amino acids as W254, leading to a competitive binding that may influence the pharmacological efficacy and potential drug interactions of sartans.
Τίτλος πηγής δημοσίευσης:	Current issues in molecular biology
Τόμος/Κεφάλαιο:	46
Τεύχος:	8
Θεματική Κατηγορία:	[EL] Βιοχημεία[EN] Biochemistry [EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry
Λέξεις-Κλειδιά:	DFT Induced-fit drug docking furin molecular dynamics sartan
Κάτοχος πνευματικών δικαιωμάτων:	© 2024 by the authors. Licensee MDPI, Basel, Switzerland.
Όροι και προϋποθέσεις δικαιωμάτων:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.3390/cimb46080486
Εμφανίζεται στις συλλογές:	Ινστιτούτο Θεωρητικής και Φυσικής Χημείας (ΙΘΦΧ) - Επιστημονικό έργο