In silico structure-based design and synthesis of novel anti-RSV compounds

Michela Cancellieri,Marcella Bassetto,Ivy Widjaja,Frank Van Kuppeveld,Cornelis A.M De Haan,Andrea Brancale

doi:10.1016/j.antiviral.2015.08.003

Michela Cancellieri, Marcella Bassetto + Show 4 more

Open Access

https://doi.org/10.1016/j.antiviral.2015.08.003

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Journal: Antiviral research	Publication Date: Aug 8, 2015
Citations: 21	License type: cc-by

Affiliation: Cardiff University, Utrecht University

Abstract

Respiratory syncytial virus (RSV) is the major cause for respiratory tract disease in infants and young children. Currently, no licensed vaccine or a selective antiviral drug against RSV infections are available. Here, we describe a structure-based drug design approach that led to the synthesis of a novel series of zinc-ejecting compounds active against RSV replication. 30 compounds, sharing a common dithiocarbamate moiety, were designed and prepared to target the zinc finger motif of the M2-1 protein. A library of ∼12,000 small fragments was docked to explore the area surrounding the zinc ion. Among these, seven ligands were selected and used for the preparation of the new derivatives. The results reported here may help the development of a lead compound for the treatment of RSV infections.

Highlights

Respiratory syncytial virus (RSV) is considered as the major cause of acute lower respiratory tract infections (ALRIs) in infants and children, causing the majority of hospitalization of young people ranging from ages 1 to 5 years old (Hall et al, 2009; RSV)
Despite the huge economic impact and the medical needs associated with severe RSV infection, no vaccine nor a specific antiviral therapy are available at the moment
The results showed the ability of this molecule to inactivate RSV at a concentration of 10 mM, presumably by modification of the M2-1 protein (Boukhvalova et al, 2010)

Summary

Introduction

Respiratory syncytial virus (RSV) is considered as the major cause of acute lower respiratory tract infections (ALRIs) in infants and children, causing the majority of hospitalization of young people ranging from ages 1 to 5 years old (Hall et al, 2009; RSV). The results showed the ability of this molecule to inactivate RSV at a concentration of 10 mM, presumably by modification of the M2-1 protein (Boukhvalova et al, 2010) Considering these data, we used a structure-based drug design approach to generate a series of compounds containing a zinc-chelating moiety. A series of docking simulations using MOE (Molecular Operating Environment, version 2009.10, Chemical Computing Group Inc.) was carried out to assess which fragments could best fit two different pocket subsites, in particular the areas that are in close proximity to the Cys3-His motif: a first region defined by Gly, Lys, His, Ser and His (Fig. 2) and a second area defined by Glu, His and Cys15 After evaluating their binding scores and interactions by a visual inspection of the generated poses, the original input database was reduced to 100 fragments, of which seven were selected according to the synthetic feasibility of the corresponding compounds. A general unsymmetrical three-membered scaffold was designed to contain a common central dithiocarbamate linker, functionalized on its two sides with different moieties that were further validated by another set of docking studies (Fig. 2)

Computer-aided design

Chemistry

Biology

Conclusion