Rational design of isonicotinic acid hydrazide derivatives with antitubercular activity: Machine learning, molecular docking, synthesis and biological testing.

The problem of designing new antitubercular drugs against multiple drug-resistant tuberculosis (MDR-TB) was addressed using advanced machine learning methods. As there are only few published measurements against MDR-TB, we collected a large literature data set and developed models against the non-resistant H37Rv strain. The predictive accuracy of these models had a coefficient of determination q2  = .7-.8 (regression models) and balanced accuracies of about 80% (classification models) with cross-validation and independent test sets. The models were applied to screen a virtual chemical library, which was designed to have MDR-TB activity. The seven most promising compounds were identified, synthesized and tested. All of them showed activity against the H37Rv strain, and three molecules demonstrated activity against the MDR-TB strain. The docking analysis indicated that the discovered molecules could bind enoyl reductase, InhA, which is required in mycobacterial cell wall development. The models are freely available online (https://ochem.eu/article/103868) and can be used to predict potential anti-TB activity of new chemicals.