Introduction: Halogens have a prominent role in drug design. Often used as a mean to improve ADME properties, they are also becoming a tool in protein–ligand recognition given their ability to form a non-covalent interaction, termed halogen bond, where halogens act as electrophilic species interacting with electron-rich partners. Rational drug design of halogen-bonding lead molecules requires an accurate description of halocarbon-protein complexes by computational tools though not all methods are able to tackle this non-covalent interaction. Areas covered: The authors present a review of computational methodologies that can be used to properly describe halogen bonds in the context of protein–ligand complexes, providing also insights on how these methods can be used in the context of computer-aided drug design. Expert opinion: Although in the last few years many computational tools, ranging from fast screening methods to the more expensive QM calculations, have been developed to tackle the halogen bonding phenomenon, they are not yet standard in the literature. This will eventually change as official software distributions are including support for halogen bonding in their methods. Tackling desolvation of halogenated species seems to be a good strategy to improve the accuracy of computational methods, that will be more commonly used prior to laboratory work in the future.

Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.