Can 'Bacterial-Metabolite-Likeness' model improve odds of 'in silico' antibiotic discovery?
'Inductive' QSAR descriptors have been used to develop the series of QSAR models enabling 'in silico' distinguishing between antimicrobial compounds, conventional drugs, and druglike substances. The constructed neural network-based models operating by 30 'inductive' parameters have been validated on an extensive set of 2686 chemical structures and resulted in up to 97% accurate separation of the three types of molecular activities. The demonstrated ability of 'inductive' parameters to adequately capture molecular features determining 'antibiotic-like' and 'druglike' potentials have been further utilized to construct a model of 'Bacterial-Metabolite-Likeness' (BML). The same 'inductive' descriptors have been used to train a neural network that could very accurately recognize substances involved into bacterial metabolism (that have been experimentally identified). When the developed model has been applied to the mixed set of antimicrobials, drugs, and druglike chemicals (not used for training the BML model), it exhibited a 2-5-fold recognition preference toward antimicrobial compounds compared to general drugs and an 18- to 45-fold preference when compared to a druglike substance (depending on the model stringency). These results illustrate immanent similarity between conventional antimicrobials and native bacterial metabolites and suggest that the developed BML model can be an effective classification tool for 'in silico' antibiotic studies.
Cherkasov
Artem
A
Division of Infectious Diseases, Faculty of Medicine, University of British Columbia, 2733 Heather Street, Vancouver, British Columbia V5Z 3J5, Canada. artc@interchange.ubc.ca
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000378:metabolism*; D016571:Neural Networks, Computer; D021281:Quantitative Structure-Activity Relationship
D000900:Anti-Bacterial Agents