title: Identification of inhibitors against the potential ligandable sites in the active cholera toxin.
abstract: The active cholera toxin responsible for the massive loss of water and ions in cholera patients via its ADP ribosylation activity is a heterodimer of the A1 subunit of the bacterial holotoxin and the human cytosolic ARF6 (ADP Ribosylation Factor 6). The active toxin is a potential target for the design of inhibitors against cholera. In this study we identified the potential ligandable sites of the active cholera toxin which can serve as binding sites for drug-like molecules. By employing an energy-based approach to identify ligand binding sites, and comparison with the results of computational solvent mapping, we identified two potential ligandable sites in the active toxin which can be targeted during structure-based drug design against cholera. Based on the probe affinities of the identified ligandable regions, docking-based virtual screening was employed to identify probable inhibitors against these sites. Several indole-based alkaloids and phosphates showed strong interactions to the important residues of the ligandable region at the A1 active site. On the other hand, 26 top scoring hits were identified against the ligandable region at the A1 ARF6 interface which showed strong hydrogen bonding interactions, including guanidines, phosphates, Leucopterin and Aristolochic acid VIa. This study has important implications in the application of hybrid structure-based and ligand-based methods against the identified ligandable sites using the identified inhibitors as reference ligands, for drug design against the active cholera toxin.
authors.affiliation: DBT Centre for Bioinformatics, Presidency University, 86/1 College Street, Kolkata - 700073, India. Electronic address: aig.bioinfo@gmail.com.
authors.forename: Aditi
authors.initials: A
authors.lastname: Gangopadhyay
authors.affiliation: Jhargram Raj College, Jhargram, Paschim Medinipur, India. Electronic address: abhijit_datta21@yahoo.com.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Datta
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000737:chemistry; D001665:Binding Sites; D002771:Cholera / Q000188:drug therapy; D002772:Cholera Toxin / Q000737:chemistry*; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000089982:ADP-Ribosylation Factor 6; D008024:Ligands; D002772:Cholera Toxin; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human
keywords: ARF6 (ADP Ribosylation Factor 6); Cholera toxin; Computational solvent mapping; Ligandability; Structure based drug design; Virtual screening