Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics
Δημιουργός/Συγγραφέας:	Ridgway, Harry Orbell, John D Matsoukas, Minos-Timotheos Kelaidonis, Konstantinos Moore, Graham J Tsiodras, Sotiris Gorgoulis, Vasilis G [EL] Χασάπης, Χρήστος[EN] Chasapis, Christos Apostolopoulos, Vasso Matsoukas, John M
Ημερομηνία:	2023
Γλώσσα:	Αγγλικά
ISSN:	2001-0370
DOI:	10.1016/j.csbj.2023.09.003
Άλλο:	37817778
Περίληψη:	Furins are serine endoproteases that process precursor proteins into their biologically active forms, and they play essential roles in normal metabolism and disease presentation, including promoting expression of bacterial virulence factors and viral pathogenesis. Thus, furins represent vital targets for development of antimicrobial and antiviral therapeutics. Recent experimental evidence indicated that dichlorophenyl (DCP)-pyridine "BOS" drugs (e.g., BOS-318) competitively inhibit human furin by an induced-fit mechanism in which tryptophan W254 in the furin catalytic cleft (FCC) functions as a molecular gate, rotating nearly 180o through a steep energy barrier about its chi-1 dihedral to an "open" orientation, exposing a buried (i.e., cryptic) hydrophobic pocket 1. Once exposed, the non-polar DCP group of BOS-318, and similar halo-phenyl groups of analogs, enter the cryptic pocket, stabilizing drug binding. Here, we demonstrate flexible-receptor docking of BOS-318 (and various analogs) was unable to emulate the induced-fit motif, even when tryptophan was replaced with less bulky phenylalanine or glycine. While either substitution allowed access to the hydrophobic pocket for most ligands tested, optimal binding was observed only for W254, inferring a stabilizing effect of the indole sidechain. Furthermore, non-equilibrium steered molecular dynamics (sMD) in which the bound drugs (or their fragments) were extracted from the FCC did not cause closure of the open W254 gate, consistent with the thermodynamic stability of the open or closed W254 orientations. Finally, interactive molecular dynamics (iMD) revealed two putative conduits of drug entry and binding into the FCC, each coupled with W254 dihedral rotation and opening of the cryptic pocket. The iMD simulations further revealed ligand entry and binding in the FCC is likely driven in part by energy fluxes stemming from disruption and re-formation of ligand and protein solvation shells during drug migration from the solution phase into the FCC.
Τίτλος πηγής δημοσίευσης:	Computational and structural biotechnology journal
Τόμος/Κεφάλαιο:	21
Θεματική Κατηγορία:	[EL] Δομική Βιολογία[EN] Structural Biology [EL] Βιοπληροφορική[EN] Bioinformatics [EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry
Λέξεις-Κλειδιά:	Antiviral Furin Induced-fit drug docking Interactive molecular dynamics SARS-CoV-2 Therapeutics
EU Grant identifier:	3782, 775 70/3/8916 MIS 5092131-action 110051339 PH098 2020ΣΕ01300001
Κάτοχος πνευματικών δικαιωμάτων:	© 2023 The Authors.
Όροι και προϋποθέσεις δικαιωμάτων:	This is an open access article under the CC BY-NC-ND license
Ηλεκτρονική διεύθυνση με ανοικτή πρόσβαση (link):	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10561063/
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1016/j.csbj.2023.09.003
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο