Structure-based virtual screening as a tool for the identification of novel inhibitors against Mycobacterium tuberculosis 3-dehydroquinate dehydratase

•Structure-based pharmacophore models of Mtb DHQase protein were established.•Pharmacophore model was validated and used as a 3D search query.•Identification of top five lead molecules after virtual screening.•In vitro enzymatic studies leads identification of top lead molecule.

3-Dehydroquinate dehydratase (DHQase), the third enzyme of the shikimate pathway, catalyzes the reversible reaction of 3-dehydroquinate into 3-dehydroshikimate. The aim of the present study was to identify new drug-like molecules as inhibitors for Mycobacterium tuberculosis DHQase employing structure-based pharmacophore modeling technique using an in house database consisting of about 2500 small molecules. Further the pharmacophore models were validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel small molecules as DHQase inhibitors. Five compounds were identified, out of which, one molecule (Lead 1) showed 58% inhibition at 50 μM concentration in the Mtb DHQase assay. Chemical derivatives of the Lead 1 when tested evolved top two hits with IC50s of 17.1 and 31.5 μM as well as MIC values of 25 and 6.25 μg/mL respectively and no cytotoxicity up to 100 μM concentration.

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