De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region.

By 2050, it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, more deaths than cancer, costing the world economy $100 trillion. Clearly, strategies to address this problem are essential as bacterial evolution is rendering our current antibiotics ineffective. The discovery of an allosteric binding site on the established antibacterial target DNA gyrase offers a new medicinal chemistry strategy. As this site is distinct from the fluoroquinolone binding site, resistance is not yet documented. Using in silico molecular design methods, we have designed and synthesised a novel series of biphenyl-based inhibitors inspired by a published thiophene-based allosteric inhibitor. This series was evaluated in vitro against Escherichia coli DNA gyrase and E. coli topoisomerase IV with the most potent compounds exhibiting IC50 values towards the low micromolar range for DNA gyrase and only ∼2-fold less active against topoisomerase IV. The structure-activity relationships reported herein suggest insights to further exploit this allosteric site, offering a pathway to overcome developing fluoroquinolone resistance.

From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor.

Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.