title: Molecular dynamics simulations and structure-based rational design lead to allosteric HCV NS5B polymerase thumb pocket 2 inhibitor with picomolar cellular replicon potency.
abstract: The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 ≤ 80 nM against gt 2-6.
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hucke
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Mégan
authors.initials: M
authors.lastname: Bertrand-Laperle
authors.forename: Christian
authors.initials: C
authors.lastname: Brochu
authors.forename: James
authors.initials: J
authors.lastname: Gillard
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Joly
authors.forename: Serge
authors.initials: S
authors.lastname: Landry
authors.forename: Olivier
authors.initials: O
authors.lastname: Lepage
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: Marc
authors.initials: M
authors.lastname: Pesant
authors.forename: Martin
authors.initials: M
authors.lastname: Poirier
authors.forename: Maude
authors.initials: M
authors.lastname: Poirier
authors.forename: Ginette
authors.initials: G
authors.lastname: McKercher
authors.forename: Martin
authors.initials: M
authors.lastname: Marquis
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Stammers
mesh_terms: D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D056004:Molecular Dynamics Simulation; D012093:Replicon / Q000187:drug effects*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase