PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Predicting Protein Crystal Candidates
October 2014
Drug Discovery: Finding Druggable Targets
October 2013
Membrane Proteome: Unveiling the Human α-helical Membrane Proteome
August 2013
Infectious Diseases: Determining the Essential Structome
May 2013
Infectious Diseases: Targeting Meningitis
May 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Targeting Enzyme Function with Structural Genomics
July 2012
Disordered Proteins
February 2012
The cancer kinome
April 2010
Learning from failure
December 2009
Dealing with difficult families
February 2009

Technology Topics Target Selection

Drug Discovery: Finding Druggable Targets

SBKB [doi:10.1038/sbkb.2012.166]
Technical Highlight - October 2013
Short description: A guide to selecting strategic targets for pharmacological intervention and drug design in microbiomes is presented for Streptococcus mutans.

A druggable target protein from S. mutans. A highly reliable structural model for uracil-diphosphate acetyl-glucosamine epimerase, shown by hydropathy plot (red as hydrophobic, blue as hydrophilic) and featuring a long, narrow pocket for drug binding. Figure courtesy of Jeremy Horst.

Genomic sequences of many bacterial species are now available, and having the entire derived proteome at hand offers many opportunities for drug development. However, one still needs to find the appropriate targets among the proteome. Horst and colleagues (PSI NYSGRC) have developed a strategy to identify potential drug targets in the bacterium Streptococcus mutans in the context of other dental plaque bacteria.

Dental caries cause irreversible damage to teeth and represent a heavy burden on global public health. Many factors contribute to the etiology of dental caries, including dietary sugars and the presence of certain bacterial species in dental plaque. While some species such as S. mutans are cariogenic, others can have a protective effect. Thus, a potential way to prevent and combat dental caries is to specifically target the cariogenic bacteria while preserving those that are non-cariogenic.

The authors followed three analytical steps to find useful drug targets among the 2,391 predicted proteins in S. mutans. First, they used MODELLER-v9.10, a restraint-based comparative modeling program, to produce models of 1,631 proteins, of which 616 were considered highly reliable (available at ModBase). Next, they assessed those 616 models along with 81 structures available in the PDB for “druggability,” i.e., the presence of favorable drug-binding sites, whittling the list to 110 proteins. Those included 15 virulence factors, 16 proteins with available crystal structures and 84 previously unidentified proteins.

Finally, the authors examined the specificity of these targets, by generating phylogenetic profiles for each of those proteins, among other cariogenic (target) and non-cariogenic (antitarget) bacteria. Unfortunately, none of the druggable proteins identified were differentially abundant among cariogenic bacteria, indicating that drugs designed against those proteins would affect the non-cariogenic species as well. This arose due to a lack of sufficient structural templates for the etiologic proteins and their control mechanisms.

It is likely that there are druggable and specific target proteins among S. mutans and other cariogenic bacteria that could not be modeled in this work. This limitation should be overcome as more protein structures become available. Nevertheless, the work provides a valuable map to streamline target selection for rational drug discovery against chronic multibacterial diseases.

Inês Chen


  1. J.A. Horst et al. Strategic protein target analysis for developing drugs to stop dental caries.
    Adv Dent Res. 24, 86-93 (2012). doi:10.1177/0022034512449837

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health