Identification of Putative “Multifunctional Drug” Against Anthrax Toxins via Integrative Computational Approach

Abstract

Background: The intentional dissemination of the “anthrax letter” led the researchers to increase their efforts towards the development of medical countermeasures against anthrax bioterrorism. A virulent strain of Bacillus anthracis secretes deadly three protein exotoxin (protective antigen, lethal factor and edema factor) that is the causative agent of anthrax and considered as serious biological weapons. Objective: Due to limited existing therapeutics options, there is still an insecure situation to combat anthrax. This prompted us to design a multifunctional inhibitor instead of a traditional one that competes simultaneously with the Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF) for their binding sites. Methods: We integrated a pharmacophore modeling approach with the virtual screening and molecular docking analysis in the context of unique structural characteristics of deadly anthrax toxins. Results: Initially, we screened 56,000 natural compounds against designed pharmacophore consensus that returned 351 hits. Out of these initial screening hits, only 100 compounds passed out through Lipinski filter that comprised of 12 chemically relevant clusters. By exclusion of duplicate and based on their fit score in each cluster, 15 unique compounds were selected for detailed study. Putative multifunctional compounds subjected to deep structural analysis in the milieu of anthrax toxins binding pockets to gauge critical structural crunch. Conclusion: Our integrative approach provides a novel therapeutic window to develop a small molecular inhibitor that simultaneously targets three components of anthrax deadly toxin at the molecular level to elicit the desired biological process.