High Throughput Structural Biology and In Silico Screening Identify Novel Antibacterial Drug Candidate

The Special Projects Group at NYSBC has built a pipeline to clone, express, purify, and determine the structures of proteins from Coxiella burnetii, a highly infectious pathogen that can cause disease in humans and other mammals. In under ten months, this group analyzed all 1847 protein-coding genes of C. burnetii, cloned 500 of these genes, purified 200 proteins to crystallization grade, and solved 48 X-ray crystal structures.

Structural information can guide the identification of more specific therapeutic agents. Left: a compound was identified by in silico screening predicted to bind the bacterial (gray) but not human (blue, steric clash in red) DHFR, and an in vitro assay confirmed this specificity.

One of the proteins, the essential enzyme dihydrofolate reductase (DHFR), was then selected as a potential drug target. Comparison with human DHFR revealed that this enzyme has a narrower substrate binding groove than the bacterial DHFR. Based on this difference, a compound was identified by in silico screening predicted to only bind the bacterial enzyme. Additionally, an in vitro assay confirmed that this compound exhibited greater specificity for the bacterial and not human DHFR.

Research article: Franklin et al. 2015, Proteins. PMID: 26033498