title: Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity.
abstract: Botulinum neurotoxins (BoNT) are among the most poisonous substances known, and of the 7 serotypes (A-G) identified thus far at least 4 can cause death in humans. The goal of this work was identification of inhibitors that specifically target the light chain catalytic site of the highly pathogenic but lesser-studied E serotype (BoNT/E). Large-scale computational screening, employing the program DOCK, was used to perform atomic-level docking of 1.4 million small molecules to prioritize those making favorable interactions with the BoNT/E site. In particular, 'footprint similarity' (FPS) scoring was used to identify compounds that could potentially mimic features on the known substrate tetrapeptide RIME. Among 92 compounds purchased and experimentally tested, compound C562-1101 emerged as the most promising hit with an apparent IC50value three-fold more potent than that of the first reported BoNT/E small molecule inhibitor NSC-77053. Additional analysis showed the predicted binding pose of C562-1101 was geometrically and energetically stable over an ensemble of structures generated by molecular dynamic simulations and that many of the intended interactions seen with RIME were maintained. Several analogs were also computationally designed and predicted to have further molecular mimicry thereby demonstrating the potential utility of footprint-based scoring protocols to help guide hit refinement.
authors.affiliation: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Graduate Program in Biochemistry & Structural Biology, Stony Brook University, Stony Brook, NY 11794, United States; Biology Department, Brookhaven National Laboratory, Upton, NY 11973, United States.
authors.forename: Brian E
authors.initials: BE
authors.lastname: McGillick
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: Yu-Han Gary
authors.initials: YG
authors.lastname: Teng
authors.affiliation: Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: Krupanandan
authors.initials: K
authors.lastname: Haranahalli
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States.
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973, United States.
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States; Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States; Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States. Electronic address: rizzorc@gmail.com.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rizzo
mesh_terms: D001905:Botulinum Toxins / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries; D001905:Botulinum Toxins; C096326:botulinum toxin type E
keywords: BoNT/E; Botulinum neurotoxin; DOCK; Docking; Footprint similarity; Molecular dynamics; Scoring functions; Virtual screening