Main Outcome Scoring function for predicting molecular permeability/accumulation
Predicting molecular permeability through the outer membrane of Gram-negative bacteria The lack of new drugs for Gram-negative pathogens is a global threat to modern medicine. The complexity of their cell envelope, with an additional outer membrane, hinders internal accumulation and thus, the access of molecules to their targets. Our limited understanding of the molecular basis for compound influx and efflux from these pathogens is a major bottleneck for the discovery of effective antibacterial compounds. My most significant contribution to the Translocation project (https://cordis.europa.eu/project/id/607694) was the design of a method to calculate the internal electric field of porins using water polarization. This method allowed us to rationalize the electrostatic sieving mechanism of porins and it culminate in the physical description of the permeation process and the development, and experimental validation of an automatic pipeline to screen and rank compounds in terms of their permeability through the outer membrane of Gram-negative bacteria. This tool addresses a major bottleneck in antibiotics drug discovery as most hits do not progress to leads due to poor permeability. Acosta-Gutiérrez et al. ACSid