Computational Drug Repurposing for Antituberculosis Therapy: Discovery of Multi-Strain Inhibitors.

Tuberculosis remains the most afflicting infectious disease known by humankind, with one quarter of the population estimated to have it in the latent state. Discovering antituberculosis drugs is a challenging, complex, expensive, and time-consuming task. To overcome the substantial costs and accelerate drug discovery and development, drug repurposing has emerged as an attractive alternative to find new applications for "old" drugs and where computational approaches play an essential role by filtering the chemical space. This work reports the first multi-condition model based on quantitative structure-activity relationships and an ensemble of neural networks (mtc-QSAR-EL) for the virtual screening of potential antituberculosis agents able to act as multi-strain inhibitors. The mtc-QSAR-EL model exhibited an accuracy higher than 85%. A physicochemical and fragment-based structural interpretation of this model was provided, and a large dataset of agency-regulated chemicals was virtually screened, with the mtc-QSAR-EL model identifying already proven antituberculosis drugs while proposing chemicals with great potential to be experimentally repurposed as antituberculosis (multi-strain inhibitors) agents. Some of the most promising molecules identified by the mtc-QSAR-EL model as antituberculosis agents were also confirmed by another computational approach, supporting the capabilities of the mtc-QSAR-EL model as an efficient tool for computational drug repurposing.