title: Computational Studies of Benzoxazinone Derivatives as Antiviral Agents against Herpes Virus Type 1 Protease.
abstract: Herpes simplex virus infections have been described in the medical literature for centuries, yet the the drugs available nowadays for therapy are largely ineffective and low oral bioavailability plays an important role on the inefficacy of the treatments. Additionally, the details of the inhibition of Herpes Virus type 1 are still not fully understood. Studies have shown that several viruses encode one or more proteases required for the production new infectious virions. This study presents an analysis of the interactions between HSV-1 protease and benzoxazinone derivatives through a combination of structure-activity relationships, comparative modeling and molecular docking studies. The structure activity relationship results showed an important contribution of hydrophobic and polarizable groups and limitations for bulky groups in specific positions. Two Herpes Virus type 1 protease models were constructed and compared to achieve the best model which was obtained by MODELLER. Molecular docking results pointed to an important interaction between the most potent benzoxazinone derivative and Ser129, consistent with previous mechanistic data. Moreover, we also observed hydrophobic interactions that may play an important role in the stabilization of inhibitors in the active site. Finally, we performed druglikeness and drugscore studies of the most potent derivatives and the drugs currently used against Herpes virus.
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. foncor@gmail.com.
authors.forename: Juliana F R
authors.initials: JF
authors.lastname: Mello
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. nathbc1991@hotmail.com.
authors.forename: Nathália C
authors.initials: NC
authors.lastname: Botelho
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. amtsouza2@yahoo.com.br.
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: Souza
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. ri_oliver@msn.com.
authors.forename: Riethe
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Laboratory of Computational Medicinal Chemistry, Faculty of Pharmacy, Fluminense Federal University, Niterói 24.241-000, RJ, Brazil. moniquebrito@id.uff.br.
authors.forename: Monique A
authors.initials: MA
authors.lastname: Brito
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. babi_abrahim@hotmail.com.
authors.forename: Bárbara de A
authors.initials: Bde A
authors.lastname: Abrahim-Vieira
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. acrsodero@gmail.com.
authors.forename: Ana Carolina R
authors.initials: AC
authors.lastname: Sodero
authors.affiliation: Laboratory of Antibiotics, Biochemistry, Education and Molecular Modeling, Institute of Biology, Fluminense Federal University, Niterói 24.210-130, RJ, Brazil. hcastrorangel@yahoo.com.br.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.affiliation: Laboratory of Industrial Pharmaceutical Technology, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. lmcabral2@ig.com.br.
authors.forename: Lucio M
authors.initials: LM
authors.lastname: Cabral
authors.affiliation: Laboratory of Antibiotics, Biochemistry, Education and Molecular Modeling, Institute of Biology, Fluminense Federal University, Niterói 24.210-130, RJ, Brazil. leossj@hotmail.com.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Miceli
authors.affiliation: Laboratory of Molecular Modeling & QSAR Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21.944-970, RJ, Brazil. rangelfarmacia@gmail.com.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D010447:Peptide Hydrolases / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D048588:Benzoxazines; D011480:Protease Inhibitors; D010447:Peptide Hydrolases
keywords: benzoxazinones; comparative modeling; herpesvirus; molecular docking; protease