The highly impermeable cell wall of M. tuberculosis (Mtb) is essential for the viability of the mycobacterium. This complex cellular envelope consists of three layers: an innermost peptidoglycan layer, an outermost mycolic acid layer, and the connecting arabinogalactan polysaccharide layer. The synthesis of an L-rhamnosyl residue, which connects the arabinogalactan and peptidoglycan layer, is an attractive target for novel anti-tuberculosis therapeutics. Employing the virtual screening (VS) approach, we identified four novel inhibitors of dTDP-deoxy-L-lyxo-4-hexulose reductase (RmlD), the last enzyme in the L-rhamnosyl synthesis pathway in Mtb. The activity of the identified compounds was verified in both protein- and cell-based assays. Comparison with an experimental high-throughput screening demonstrates that VS produces a better hit rate. Additionally, through evaluating the performance of database enrichment, we discuss the role of molecular dynamics simulations in incorporating receptor flexibility into computer-aided drug design.

Computer-aided drug design targeting the <i>M. tuberculosis</i> enzyme RmlD

243rd National Meeting (2012)

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Computer-aided drug design targeting the M. tuberculosis enzyme RmlD