title: Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors.
abstract: The β-OG pocket is a cavity in the flavivirus envelope (E) protein that was identified by Proc. Natl. Acad. Sci. U.S.A.2003, 100, 6986 as a promising site for the design of antiviral agents that interfere with virus entry into the host cell. The availability of the X-ray crystal structure of the dengue virus (DENV) E protein provided an opportunity for in silico drug design efforts to identify candidate inhibitors. The present study was set up to explore whether it is possible to generate a novel class of molecules that are hybrids between two hit compounds that have been reported previously by ACS. Chem. Biol.2008, 3, 765 following an in silico screening effort against the DENV E protein. First, a library of twenty hybrid molecules were designed and synthesized to explore the feasibility of this strategy. Antiviral evaluation in a virus-cell-based assay for DENV proved this approach to be successful, after which another twenty-four molecules were produced to further explore and optimize the potency of this novel class of hybrid inhibitors. In the end, a molecule was obtained with an EC50 against dengue virus serotype 2 in the low micromolar range (23, 1.32±0.41μM).
authors: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India.
authors: Surender Singh
authors: SS
authors: Jadav
authors: Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium.
authors: Suzanne
authors: S
authors: Kaptein
authors: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India.
authors: Ajaykumar
authors: A
authors: Timiri
authors: Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium.
authors: Tine
authors: T
authors: De Burghgraeve
authors: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India.
authors: Vishnu Nayak
authors: VN
authors: Badavath
authors: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India.
authors: Ramesh
authors: R
authors: Ganesan
authors: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India.
authors: Barij Nayan
authors: BN
authors: Sinha
authors: Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium. Electronic address: Johan.Neyts@rega.kuleuven.be.
authors: Johan
authors: J
authors: Neyts
authors: Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium.
authors: Pieter
authors: P
authors: Leyssen
authors: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India. Electronic address: venkatesanj@bitmesra.ac.in.
authors: Venkatesan
authors: V
authors: Jayaprakash
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003716:Dengue Virus / Q000378:metabolism*; D015195:Drug Design; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012545:Schiff Bases / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011720:Pyrazoles; D012545:Schiff Bases; D013844:Thiazoles; D014759:Viral Envelope Proteins
keywords: Dengue virus; E protein; Pyrazolines; Schiff’s bases; Thiazoles