Identification of potential inhibitors of shikimate kinase from Mycobacterium tuberculosis using in silico approach

Shikimate kinase is an enzyme that plays a crucial role in the biosynthesis of aromatic amino acids. It is integral to the fifth step of the shikimate pathway, transferring a phosphoryl group from ATP to shikimate, yielding ADP and shikimate-3-phosphate within Mycobacterium tuberculosis (Mtb). This enzyme is an attractive target for drug discovery, especially against pathogens like Mtb that rely on this pathway. The research aimed to identify innovative inhibitors for Mtb by exploring various naturally occurring and synthetic compounds using an in silico approach. The 3D structure of SK complexed with ligands (EPE), ADP, and essential cofactors (Mg²⁺, Cl⁻, Pt⁺) was obtained from the Protein Data Bank. From public databases (Zinc Database and PubChem), 11,323 compounds were identified, showing potential binding affinity to SK with strong binding affinities. These compounds were carefully filtered using Lipinski’s rule of five and underwent molecular docking and ADMET analyses. Compounds PubChem15478 (− 11.75 kcal/mol), ZINC02838601 (− 11.52 kcal/mol), and ZINC11790367 (− 9.88 kcal/mol) had the best binding energies. These compounds demonstrated favorable physicochemical properties and ADMET profiles. The selected compounds then underwent extensive MD simulations analysis. Concurrently, MD simulations involving SK in conjunction with EPE, ADP, and Mg²⁺ were performed to evaluate their stability relative to protein–ligand complexes. Encouragingly, two compounds—ZINC11790367 and PubChem15478—formed robust and unyielding complexes, resembling the behavior of bound ligands and cofactors during 50 ns MD simulations. This evidence suggests that these compounds have potential as effective SK inhibitors for Mtb, pending successful experimental validation.