Poster Presenter

Discovery of New Ligands For Protein Kinase Pknb From Mycobacterium Tuberculosis Based On Mitoxantrone
A. Naqvi, H. Beg, E.Manivannan
India

Protein kinases B (PKnB) plays an important role in mammalian cellular signaling. Mycobacterium tuberculosis PknB is an essential receptor-like protein kinase involved in cell growth control and is a trans-membrane Ser/Thr protein kinase (STPK) highly conserved in Gram-positive bacteria and apparently essential for mycobacterial viability. Mitoxantrone, an anthraquinone derivative used in cancer treatment, is a PKnB inhibitor capable of preventing mycobacterial cell growth, suggesting that bacterial kinases may also represent a potential target for drug design. The structure of the complex reveals that mitoxantrone partially occupies the adenine-binding pocket in PKnB, providing a framework for the design of compounds with potential therapeutic applications.

We have attempted with the help of docking and dynamics approach to elucidate the extent of specificity of protein kinase B towards different classes of mitoxantrone. Out of 48 mitoxantrones from three different databases, we report Mepixanox and Silymarin as the best molecules structurally that showed better binding energies and favorable dynamics for a time period of 40ps. Again on the basis of structure similarity of Mepixanox and Silymarin 36 molecules were selected and docking was performed using Lamarckian Genetic Algorithm. Our docking result demonstrated that the binding energies were in the range from -9.94 kcal/ mol to -8.58 kcal/mol and 3 molecules, structure similarity as of Mepixanox and 5 molecules, structure similarity as of Silymarin showed minimum binding energies from -9.94 kcal/mol to -9.92 kcal/mol. These molecules also showed favorable dynamics over a time period of 40ps. The PknB peptide contains two types of structural elements (valine 95, arginine 97) and basic residue ring constituted of glycine rich residue.

Our study gives an idea about the interaction between the active site residues and the substrate which is explained on the basis of size & hydrophobicity of the binding pocket. The molecules that we report here follow Lipinski's rule of 5 and are not yet tested in the laboratory and the autoflourescence data for these molecules is not available. There is need to generate in vitro and in vivo activity of the generated data to synthesize and test so to design new drugs with better specificity and metabolism.