Identification of small molecule inhibitors of botulinum neurotoxin serotype E via footprint similarity. Issue 20 (15th October 2016)

• Record Type: Journal Article
• Authors: Zhou, Yuchen; McGillick, Brian E.; Teng, Yu-Han Gary; Haranahalli, Krupanandan; Ojima, Iwao; Swaminathan, Subramanyam; Rizzo, Robert C.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 20(2016)
• Page Start: 4875
• Page End: 4889
• Publication Date: 2016-10-15
• Subjects: BoNT/E botulinum neurotoxin serotype E -- FPS footprint similarity -- DCE DOCK Cartesian energy -- VDW van der Waals -- ES electrostatic -- MD molecular dynamics; Botulinum neurotoxin -- BoNT/E -- Docking -- Virtual screening -- DOCK -- Footprint similarity -- Scoring functions -- Molecular dynamics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.07.031
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 IC50 value 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.