Discovery of new inhibitors of Mycobacterium tuberculosis EPSP synthase - A computational study

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Tuberculosis (TB) is a highly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). EPSP Synthase (MtEPSPS), the enzyme responsible for the sixth step of the shikimate pathway, is a potential target for the development of new drugs for the treatment of TB, as it is essential in mycobacteria but absent in humans. In this work, we performed virtual screening using sets of molecules from two databases and three crystallographic structures of MtEPSPS. The initial hits obtained from molecular docking were filtered based on predicted binding affinity and interactions with binding site residues. Subsequently, molecular dynamics simulations were carried out to analyze the stability of protein-ligand complexes. We have found that MtEPSPS forms stable interactions with several candidates, including already approved pharmaceutical drugs such as Conivaptan and Ribavirin monophosphate. In particular, Conivaptan had the highest estimated binding affinity with the open conformation of the enzyme. The complex formed between MtEPSPS and Ribavirin monophosphate was also energetically stable as shown by RMSD, Rg and FEL analyses, and the ligand was stabilized by hydrogen bonds with important residues of the binding site. The findings reported in this work could serve as the basis of promising scaffolds for the discovery, design, and development of new anti-TB drugs.