INTRODUCTION: Present-day rational drug design approaches are based on 
exploiting unique features of the target biomolecules, small- or macromolecule 
drug candidates and physical forces that govern their interactions. The 2013 
Nobel Prize in chemistry awarded 'for the development of multiscale models for 
complex chemical systems' once again demonstrated the importance of the tailored 
drug discovery that reduces the role of the trial-and-error approach to a 
minimum. The intentional dissemination of Bacillus anthracis spores in 2001 via 
the so-called anthrax letters has led to increased efforts, politically and 
scientifically, to develop medical countermeasures that will protect people from 
the threat of anthrax bioterrorism.
AREAS COVERED: This article provides an overview of the recent rational drug 
design approaches for discovering inhibitors of anthrax toxin. The review also 
directs the readers to the vast literature on the recognized advances and future 
possibilities in the field.
EXPERT OPINION: Existing options to combat anthrax toxin lethality are limited. 
With the only anthrax toxin inhibiting therapy (protective antigen-targeting 
with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, 
the situation, in our view, is still insecure. Further, the FDA's animal rule 
for drug approval, which clears compounds without validated efficacy studies on 
humans, creates a high level of uncertainty, especially when a 
well-characterized animal model does not exist. Better identification and 
validation of anthrax toxin therapeutic targets at the molecular level as well 
as elucidation of the parameters determining the corresponding therapeutic 
windows are still necessary for more effective therapeutic options.