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Review
. 2016 Oct:30:116-130.
doi: 10.1016/j.coph.2016.08.014. Epub 2016 Sep 6.

Structural biology in antiviral drug discovery

Marcella Bassetto  1 , Alberto Massarotti  2 , Antonio Coluccia  3 , Andrea Brancale  4
Affiliations
Review

Structural biology in antiviral drug discovery

Marcella Bassetto et al. Curr Opin Pharmacol. 2016 Oct.

Abstract

Structural biology has emerged during the last thirty years as a powerful tool for rational drug discovery. Crystal structures of biological targets alone and in complex with ligands and inhibitors provide essential insights into the mechanisms of actions of enzymes, their conformational changes upon ligand binding, the architectures and interactions of binding pockets. Structure-based methods such as crystallographic fragment screening represent nowadays invaluable instruments for the identification of new biologically active compounds. In this context, three-dimensional protein structures have played essential roles for the understanding of the activity and for the design of novel antiviral agents against several different viruses. In this review, the evolution in the resolution of viral structures is analysed, along with the role of crystal structures in the discovery and optimisation of new antivirals.

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Figures

Figure 1
Figure 1
Statistical details of 7852 PDB entries considered. RCSB Protein Data Bank was used to retrieve the viral PDB entries using ‘TAXONOMY is Viruses’ as a search string. (a) Taxonomy, (b) detailed taxonomy, (c) experimental method, and (d) resolutions.
Figure 2
Figure 2
Growth in the numbers of viral PDB entries. The large increase shown from 1984 was due to the release of the tomato bushy stunt virus (PDB id: 2tbv) [13]. (a) Total number of entries, (b) details of viruses reported more than 50 times.
Figure 3
Figure 3
Analysis of the top viruses in the PDB versus the corresponding publications in PubMed.
Figure 4
Figure 4
HIV-1 RT structure (PDB ID: 5D3G), p66 and p55 subunits are depicted in light green and light orange, respectively.
Figure 5
Figure 5
Chemical structures of HIV-1 RT inhibitors discovered or optimised using structure-based methods.
Figure 6
Figure 6
Chemical structures of non-nucleoside inhibitors of the HCV NS5B polymerase discovered or optimised with structure-based methods.
Figure 7
Figure 7
Chemical structures of influenza endonuclease inhibitors 14a–b and Dengue polymerase inhibitors 15a–b.
Figure 8
Figure 8
Chemical structures of enterovirus 71 and norovirus inhibitors discovered with the aid of structural methods.
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