Design of novel quinoline-aminopiperidine derivatives as <i>Mycobacterium tuberculosis</i> (MTB) GyrB inhibitors: an <i>in silico</i> study

<p>Tuberculosis (TB) is an infectious disease that causes a number of deaths, and the development of new, safer and more adequate TB inhibitors/drugs has become a necessity as well as a great challenge. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of anti-tubercular drug discovery. To design the novel and potent <i>Mycobacterium tuberculosis</i> (MTB) inhibitors, we performed molecular modeling studies that combined the 3D-QSAR, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Forty eight quinoline-aminopiperidine inhibitors which act on DNA gyrase B subunit were used for constructing 3D-QSAR models. The results showed that the best CoMFA model had the high performance with <i>q</i>² <i>=</i> 0.643, <i>r² = 0.947</i>, while the best CoMSIA model yielded <i>q</i>² <i>=</i> 0.536, <i>r</i>²<i> = </i>0.948. The contour map was in good agreement with the docking and MD simulations which strongly demonstrated that the molecular modeling was reliable. Based on this information, several potential compounds were designed and their inhibitory activities were also verified by the accomplished models and ADME/T predictions. We hope that our research could bring new ideas to facilitate the development of novel inhibitors with higher inhibitory activity for TB.</p> <p>Communicated by Ramaswamy H. Sarma