Inhibitory Activity of Betulin (Lup-20(29)-Ene-3β, 28-Diol) On Pknb Serine/Threonine Kinase from Mycobacterium Tuberculosis : A Molecular Modeling Study

Ser/Thr Kinase is one of the four M. tuberculosis kinases that are conserved in the downsized genome of Mycobacterium leprae and are therefore presumed to play an important role in the processes that regulate the c omplex life cycle of mycobacteria. It is known that there are two main superfamilies of prot ein kinases, one including STPKs1 and PTKs and that of His kinases. For a long time, the former were only found in eukaryotes, and the latter were only found in proka ryotes. In this paradigm, proteins from each superfamily were supposed to play analogous roles in the essentially different organization of signal transduction in both phyla. In this study we report the binding mode of Ser/Thr kinase with derivatives of Betulin ((lup-20(29)-ene-3β,28-diol) on the basis of structural similarity, substructure, isom ers & conformers. Molecular docking approach using Lamarckian Genetic Algorithm was carried out to find out the potent inhibitors for Ser/Thr Kinase on the basis of calcu lated ligand-protein pairwise interaction energies. Study was carried out on 3000 molecules which were virtually screened from different databases on the basis of t he structural similarity of Betulin. The grid maps representing the protein were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. Docking was carried out with standard docking protocol on the basis of a population size of 150 randomly placed individuals; a maximum number of 2.5 *107 energy evaluations, a mutation rate of 0.02, a crossover rate of 0.80 and an elitism value of 1. Fifteen ind ependent docking runs were carried out for each ligand and results were clustered accordin g to the 1.0 Ǻ rmsd criteria. The docking result of the study of 3000 molecules d emonstrated that the binding energies were in the range of -12.72 kcal/mol to -1.71 kcal/ mol, with the minimum binding energy of ‐12.72 kcal/mol. 6 molecules showing hydrogen bonds with the active site residue VAL 95. Further in-vitro and in-vivo study is requi red on these molecules as the binding mode provided hints for the future design of new de rivatives with higher potency and specificity.