Computer aided molecular design of DPRE1 and PKNB inhibitors as highly potential anti-tuberculosis agents

Computer-aided molecular design approaches are useful tools in the discovery and optimization of novel drug targets due to their quick speed and high efficiency. In this study computer-aided molecular design, including ligand-based drug design and structure-based drug design approaches, were applied to understand the molecular basis in the development of novel and more potent anti-tuberculosis agents. Decaprenylphosphoryl-β-d-ribose 2’-epimerase (DprE1) and Serine/Threonine protein kinases B (PknB) inhibitors as anti-tuberculosis agents were selected for investigation. The first inhibitor, 4-aminoquinolone piperidine amide derivatives (AQs), were developed as non-covalent inhibitors. To gain the structural basis to improve the biological activity of DprE1 inhibitors, three dimensional quantitative structure activity relationship (3D-QSAR), molecular docking calculations, and molecular dynamic (MD) simulations were applied to elucidate the important information. The results from 3D- QSAR molecular docking calculations and MD simulations provided beneficial information at molecular levels and guidelines for the design of new and more potent DprE1 inhibitors. The second inhibitor was PknB. This is an essential enzyme for mycobacterium tuberculosis growth and was identified as a promising target. Molecular docking calculation and MD simulations were used to elucidate the binding mode, crucial interaction, and binding energy of PknB inhibitors for the rational design of more potent PknB inhibitors. The integrated results from molecular docking calculations and MD simulations provided key structural features and beneficial guidelines for the design of new and more potent PknB inhibitors. Consequently, the results from the structure-based and ligand –based design approaches can provide structural information at the molecular level which is a guideline for the design of effective anti-tuberculosis agents of high potentiality.