Vasyl Kovalishyn, Volodymyr Brovarets, Volodymyr Blagodatnyi, Iryna Kopernyk, Diana Hodyna, Svitlana Chumachenko, Oleg Shablykin, Oleksandr Kozachenko, Myhailo Vovk, Marianna Barus, Myhailo Bratenko and Larysa Metelytsia Pages 25 - 38 ( 14 )
Background: The increasing rate of appearance of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) is a serious problem at the present time. MDR-TB forms do not respond to the standard treatment with the commonly used drugs and can take some years or more to treat with drugs that are less potent, more toxic and much more expensive.Objective: The goal of this work is to identify the novel effective drug candidates active against MDR-TB strains through the use of methods of cheminformatics and computeraided drug design. Methods: This paper describes Quantitative Structure-Activity Relationships (QSAR) studies using Artificial Neural Networks, synthesis and in vitro antitubercular activity of several potent compounds against H37Rv and resistant Mycobacterium tuberculosis (Mtb) strains. Results: Eight QSAR models were built using various types of descriptors with four publicly available structurally diverse datasets, including recent data from PubChem and ChEMBL. The predictive power of the obtained QSAR models was evaluated with a cross-validation procedure, giving a q2=0.74-0.78 for regression models and overall accuracy 78.9-94.4% for classification models. The external test sets were predicted with accuracies in the range of 84.1-95.0% (for the active/inactive classifications) and q2=0.80- 0.83 for regressions. The 15 synthesized compounds showed inhibitory activity against H37Rv strain whereas the compounds 1-7 were also active against resistant Mtb strain (resistant to isoniazid and rifampicin). Conclusion: The results indicated that compounds 1-7 could serve as promising leads for further optimization as novel antibacterial inhibitors, in particular, for the treatment of drug resistance of Mtb forms.
Drug design, QSAR, Artificial Neural Networks, Mycobacterium tuberculosis.
Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Science of Ukraine, 1 Murmanska Street, 02660, Kyiv