Virtual Screening Identifies Novel and Potent Inhibitors of PknB with Antibacterial Activity

protein 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 PknB from the Specs compound library (www.specs.net). Fifteen compounds were identified as hits and selected for biological assays, of which three indoles (, AE-848/42799159; , AH-262/34335013; , AP-124/40904362) inhibited growth of H37Rv with minimal inhibitory concentrations of 6.2, 12.5, and 6.2 μg/mL, respectively. Two compounds, and , inhibited PknB activity , with IC values of 14.4 and 12.1 μM, respectively, suggesting this to be the likely basis of their anti-tubercular activity. In contrast, compound displayed anti-tuberculosis activity against H37Rv but showed no inhibition of PknB activity (IC > 128 μM). We hypothesize that hydrolysis of its ethyl ester to a carboxylate moiety generates an active species that inhibits other enzymes. Molecular dynamics simulations of modeled complexes of compounds , , and bound to PknB indicated that compound has a lower affinity for PknB than compounds and , as evidenced by higher calculated binding free energies, consistent with experiment. Compounds and therefore represent candidate inhibitors of PknB that provide attractive starting templates for optimization as anti-tubercular agents.