The year 2018 witnessed half a million new cases of drug-resistant tuberculosis (TB) according to WHO’s latest Global TB Report. The situation calls for the development of new drugs acting on unexplored targets to combat drug-resistant TB. MraY (phospho-MurNAc-pentapeptide translocase or translocase I), a membrane-bound protein that plays a key role in peptidoglycan biosynthesis of bacterial cell walls, is an unexploited target for chemotherapeutics development. Nucleoside-based natural products that target MraY suffer from various challenges and examples of non-nucleoside MraY inhibitors are very scarce in the literature. Recent reports of the X-ray crystal structures of MraY bound with nucleoside containing inhibitors have improved our understanding of the binding mechanism of the ligands with the protein and associated conformational changes. To identify new non-nucleoside inhibitors of MraYMtb we have employed a protein-structure-based virtual screening (VS) approach. Because no MraYMtb crystal structure is available, homology models of MraYMtb were constructed and were further refined by performing molecular dynamics simulation (100 ns) with muraymycin D2 (MD2) complex. Using the ZINC15 database, ~12 million commercially available compounds were screened against the MraYMtb homology model using GOLD software. 40 hits were identified based on the ChemScore function, clustering, and visual inspection of ligand interactions with MraYMtb. Finally, sixteen hits were purchased on the basis of cost and availability and evaluated against Mtb growth. The in-vitro screening (MABA assay) yielded three hits which showed efficacy in restraining Mtb growth. These identified hits are being further used in structure-based drug design to identify novel and potent non-nucleoside MraYMtb inhibitors for TB and other drug-resistant infections.

Structure-based virtual screening approach to identify new MraY inhibitors for tuberculosis chemotherapy

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.