title: Highly predictive support vector machine (SVM) models for anthrax toxin lethal factor (LF) inhibitors.
abstract: Anthrax is a highly lethal, acute infectious disease caused by the rod-shaped, Gram-positive bacterium Bacillus anthracis. The anthrax toxin lethal factor (LF), a zinc metalloprotease secreted by the bacilli, plays a key role in anthrax pathogenesis and is chiefly responsible for anthrax-related toxemia and host death, partly via inactivation of mitogen-activated protein kinase kinase (MAPKK) enzymes and consequent disruption of key cellular signaling pathways. Antibiotics such as fluoroquinolones are capable of clearing the bacilli but have no effect on LF-mediated toxemia; LF itself therefore remains the preferred target for toxin inactivation. However, currently no LF inhibitor is available on the market as a therapeutic, partly due to the insufficiency of existing LF inhibitor scaffolds in terms of efficacy, selectivity, and toxicity. In the current work, we present novel support vector machine (SVM) models with high prediction accuracy that are designed to rapidly identify potential novel, structurally diverse LF inhibitor chemical matter from compound libraries. These SVM models were trained and validated using 508 compounds with published LF biological activity data and 847 inactive compounds deposited in the Pub Chem BioAssay database. One model, M1, demonstrated particularly favorable selectivity toward highly active compounds by correctly predicting 39 (95.12%) out of 41 nanomolar-level LF inhibitors, 46 (93.88%) out of 49 inactives, and 844 (99.65%) out of 847 Pub Chem inactives in external, unbiased test sets. These models are expected to facilitate the prediction of LF inhibitory activity for existing molecules, as well as identification of novel potential LF inhibitors from large datasets.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN 55414-2959, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN 55414-2959, United States; Minnesota Supercomputing Institute for Advanced Computational Research, 117 Pleasant St SE, Minneapolis, MN, United States. Electronic address: eamin@umn.edu.
authors.forename: Elizabeth Ambrose
authors.initials: EA
authors.lastname: Amin
mesh_terms: D000931:Antidotes / Q000737:chemistry*; D000942:Antigens, Bacterial / Q000737:chemistry; D001408:Bacillus anthracis / Q000737:chemistry* / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D062126:Databases, Chemical; D057166:High-Throughput Screening Assays; D008956:Models, Chemical; D015233:Models, Statistical; D011237:Predictive Value of Tests; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D060388:Support Vector Machine; D014584:User-Computer Interface
chemical_list: D000931:Antidotes; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D054852:Small Molecule Libraries; C030325:anthrax toxin
keywords: Anthrax; Anthrax toxin lethal factor; SVM; Support vector machine