title: Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors.
abstract: Development of antivirals for dengue is now based on rational approach targeting the enzymes involved in its life cycle. Among the targets available for inhibition of dengue virus, non-structural protein NS2B-NS3 protease is considered as a promising target for the development of anti-dengue agents. In the current study we have synthesized a series of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzene-1-sulphonamide derivatives and screened for DENV2 protease activity. Compounds 16 and 19 showed IC50 of DENV2 Protease activity with 48.2 and 121.9μM respectively. Molecular docking and molecular dynamic simulation studies were carried out to know the binding mode responsible for the activity. MD simulations revealed that, NS2B/NS3 protease was more stable when it binds with the active compound. Structure optimization of the lead compounds 16 and 19 and their co-crystallization studies are underway.
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Timiri
authors.affiliation: Centre for Advanced Study in Crystallography and Biophysics, University of Madras, Chennai 600 025, Tamil Nadu, India.
authors.forename: Subasri
authors.initials: S
authors.lastname: Selvarasu
authors.affiliation: Centre for Advanced Study in Crystallography and Biophysics, University of Madras, Chennai 600 025, Tamil Nadu, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Kesherwani
authors.affiliation: Centre for Advanced Study in Crystallography and Biophysics, University of Madras, Chennai 600 025, Tamil Nadu, India.
authors.forename: Vishwanathan
authors.initials: V
authors.lastname: Vijayan
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
authors.forename: Barij Nayan
authors.initials: BN
authors.lastname: Sinha
authors.affiliation: Centre for Advanced Study in Crystallography and Biophysics, University of Madras, Chennai 600 025, Tamil Nadu, India.
authors.forename: Velmurugan
authors.initials: V
authors.lastname: Devadasan
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India. Electronic address: venkatesanj@bitmesra.ac.in.
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Jayaprakash
mesh_terms: D003716:Dengue Virus; D057075:Enzyme Assays; D057166:High-Throughput Screening Assays; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010797:Phthalimides; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000085242:Viral Proteases
chemical_list: D007211:Indoles; D009281:Naphthalenes; D010797:Phthalimides; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D013449:Sulfonamides; C000607265:4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl)benzenesulphonamide; C000607266:4-(1,3-dioxoisoindolin-2-yl)-N-(naphthalen-1-yl)benzenesulphonamide; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: Antiviral; Dengue; Molecular docking; Molecular interactions; NS2B–NS3 protease; Phthalimide; Sulphonamides