Search for novel anti-tubercular drug by virtual screening of ligands against EPSP Synthase enzyme from Mycobacterium tuberculosis

Pramod Kumar Sahu, Mukesh Kumar Raval


Objective: Shikimate pathway is a seven steps metabolic process for the amino acid biosynthesis. This is a potential target for the development of new drugs against Mycobacterium tuberculosis because the pathway is present in the microorganism but absent in mammals. ZINC provides a very large data base and a structure-based virtual screening is used for the discovery of lead.

Methods: Each step in the shikimate pathway is enzyme catalysed. Enolpyruvyl shikimate-3-phosphate synthase (EPSPS) catalysed the sixth step in which shikimate-3- phosphate (S3P) with Phosphoenolpyruvate (PEP) converted to 5-enolpyruvyl-shikimate-3-phosphate by aroA gene. Ligands in ZINC database are screened for the active binding site of EPSPS enzyme using i-dock and Arguslab. About 13000 numbers of ligands were docked in EPSPS enzyme.

Results: Best ten out of 1000 hits are considered to select leads. These hits are docked with Arguslab and almost all score better than the natural ligand shikimate-3-phosphate. These best ten hits are analysed through FAF-Drug3 and Molsoft online tool for their drug-likeness. Then oral toxicity is tested by using ProTox online tool. Only one from the list of hits passing the drug-likeness and toxicity test is considered as lead. The lead molecule is optimised by in silico modification of functional groups using Hyperchem. About fifteen derivatives were prepared and again docked using Arguslab. Similarly the Molsoft for drug-likeness and Protox for oral toxicity test were done for the derivatives.

Conclusions: About 13000 ligands from ZINC database were docked in the enzyme EPSP synthase. Out of these only two i.e. derivative-6 and 7 yield the desired result. Hence these two compounds can be considered for anti-mycobacterium tuberculosis potential drugs which required further in vitro and in vivo validation study.


Enolpyruvyl Shikimate-3-phosphate¸ shikimate-3- phosphate, Phosphoenolpyruvate, i-dock, Arguslab, Molsoft, ProTox

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