title: Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design.
abstract: The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokokawa
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Shahul
authors.initials: S
authors.lastname: Nilar
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Noble
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Ranga
authors.initials: R
authors.lastname: Rao
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Stefani
authors.initials: S
authors.lastname: Tania
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Gladys
authors.initials: G
authors.lastname: Lee
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Jürg
authors.initials: J
authors.lastname: Hunziker
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Ratna
authors.initials: R
authors.lastname: Karuna
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Ujjini
authors.initials: U
authors.lastname: Manjunatha
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.|Department of Biochemistry & Molecular Biology, Department of Phamarcology & Toxicology, Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch , Galveston, Texas 77555, United States.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002151:Calorimetry; D002460:Cell Line; D003716:Dengue Virus / Q000201:enzymology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D020349:Surface Plasmon Resonance
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012324:RNA-Dependent RNA Polymerase