Simulations of Shikimate Dehydrogenase from Mycobacterium tuberculosis in Complex with 3-Dehydroshikimate and NADPH Suggest Strategies for MtbSDH Inhibition

Shikimate dehydrogenase (SDH) from Mycobacterium tuberculosis (MtbSDH), encoded by the aroE gene, is essential for viability of M. tuberculosis but absent from humans. Therefore, it is a potentially promising target for antituberculosis agent development. Molecular-level understanding of the interactions of MtbSDH with its 3-dehydroshikimate (DHS) substrate and NADPH cofactor will help in the design of novel and effective MtbSDH inhibitors. However, this is limited by the lack of relevant crystal structures for MtbSDH complexes. Here, molecular dynamics (MD) simulations were performed to generate these MtbSDH complexes and investigate interactions of MtbSDH with substrate and cofactor and the role of MtbSDH dynamics within these. The results indicate that, while structural rearrangements are not necessary for DHS binding, reorientation of individual side chains in the NADPH binding pocket is involved in ternary complex formation. The mechanistic roles for Lys69, Asp105, and Ala213 were investigated by gen...