A Molecular Dynamics Investigation of Mycobacterium tuberculosis Prenyl Synthases: Conformational Flexibility and Implications for Computer-aided Drug Discovery.

With the rise in antibiotic resistance, there is interest in discovering new drugs active against new targets. Here, we investigate the dynamic structures of three isoprenoid synthases from Mycobacterium tuberculosis using molecular dynamics (MD) methods with a view to discovering new drug leads. Two of the enzymes, cis-farnesyl diphosphate synthase (cis-FPPS) and cis-decaprenyl diphosphate synthase (cis-DPPS), are involved in bacterial cell wall biosynthesis, while the third, tuberculosinyl adenosine synthase (Rv3378c), is involved in virulence factor formation.

Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC.

While it is well established that protonation and tautomeric states of ligands can significantly affect the results of virtual screening, such effects of ionizable residues of protein receptors are less well understood. In this study, we focus on histidine protonation and rotameric states and their impact on virtual screening of Mycobacterium tuberculosis enzyme RmlC. Depending on the net charge and the location of proton(s), a histidine can adopt three states: HIP (+1 charged, both δ- and ε-nitrogens protonated), HID (neutral, δ-nitrogen protonated), and HIE (neutral, ε-nitrogen protonated).