부산대학교 도서관

Mycobacterium tuberculosisprotein kinase B (PknB) is essential to mycobacterial growth and has received considerable attention as an attractive target for novel anti-tuberculosis drug development. Here, virtual screening, validated by biological assays, was applied to select candidate inhibitors of M. tuberculosisPknB from the Specs compound library (www.specs.net). Fifteen compounds were identified as hits and selected for in vitrobiological assays, of which three indoles (2, AE-848/42799159; 4, AH-262/34335013; 10, AP-124/40904362) inhibited growth of M. tuberculosisH37Rv with minimal inhibitory concentrations of 6.2, 12.5, and 6.2 μg/mL, respectively. Two compounds, 2and 10, inhibited M. tuberculosisPknB activity in vitro, with IC50values of 14.4 and 12.1 μM, respectively, suggesting this to be the likely basis of their anti-tubercular activity. In contrast, compound 4displayed anti-tuberculosis activity against M. tuberculosisH37Rv but showed no inhibition of PknB activity (IC50> 128 μM). We hypothesize that hydrolysis of its ethyl ester to a carboxylate moiety generates an active species that inhibits other M. tuberculosisenzymes. Molecular dynamics simulations of modeled complexes of compounds 2, 4, and 10bound to M. tuberculosisPknB indicated that compound 4has a lower affinity for M. tuberculosisPknB than compounds 2and 10, as evidenced by higher calculated binding free energies, consistent with experiment. Compounds 2and 10therefore represent candidate inhibitors of M. tuberculosisPknB that provide attractive starting templates for optimization as anti-tubercular agents.