A Structure-Activity Relationship Study of Naphthoquinone Derivatives as Antitubercular Agents Using Molecular Modeling Techniques

Tuberculosis (TB) is one of the major causes of death worldwide. Mycobacterium tuberculosis, the leading causative agent of TB, is responsible for the morbidity and mortality of a large population worldwide. In view of above and as a part of our effort to develop new and potent anti-TB agents, a series of substituted naphthoquinone derivatives were subjected to molecular modeling using various feature selection methods. The statistically significant best 2D-QSAR model having correlation coefficient r(2) = 0.8643 and cross-validated squared correlation coefficient q(2) = 0.7138 with external predictive ability of pred r(2) = 0.7420 was developed by SA-PLS, and group-based QSAR model having r(2) = 0.7964 and q(2) = 0.7550 with pred r(2) = 0.7293 was developed by SA-PLS. Further analysis using three-dimensional QSAR technique identifies a suitable model obtained by SA-partial least square method leading to antitubercular activity prediction. k-nearest neighbor molecular field analysis was used to construct the best 3D-QSAR model using SA-PLS method, showing good correlative and predictive capabilities in terms of q(2) = 0.7863 and pred r(2) = 0.7396. The pharmacophore analysis results obtained from this study show that the distance between the aromatic/hydrophobic and the naphthoquinone moiety sites to the aliphatic and acceptor groups should be connected with almost the same distance for significant antitubercular activity. The information rendered by QSAR models may lead to a better understanding of structural requirements of antitubercular activity and also can help in the design of novel potent antitubercular activity.