Investigating the interaction pattern of FDA approved compounds with Mycobacterium tuberculosis GidB to understand...

Mycobacterium tuberculosis (M.tb) drug resistance is a major challenge in eradicating its infection globally. M.tb is continuously evolving to overcome the anti-TB drug stress and retain its survival inside the host cells. This continuous evolution of M.tb can only be tackled by the continuous search for novel drug targets as well as developing new therapeutics. Using computational-based approaches we analyzed the potential of 2449 different FDA-approved drugs to interact and bind with GidB (Rv3919c), a key methyltransferase responsible for rRNA methylation in M.tb. Using molecular docking technique, we analyzed the binding energy and the potential affinity of the compounds to the molecular target GidB. Molecular dynamics simulations were performed to investigate the stability of the top-docked compounds and their crucial interactions throughout the 100 ns simulation period. Medronic acid, Arbutin, Oxidronic acid, Pamidronic acid, Dipyrithione, and Zoledronic acid are the 6 top FDA-approved compounds recorded to have high binding affinity for GidB. However, only 4 of these namely, Medronic acid, Arbutin, Dipyrithione, and Zoledronic acid were found to make stable interactions. This initial study put forward the stable interactors of M.tb GidB that could be efficient inhibitors of this key enzyme. Future comprehensive in vitro and in vivo investigations of these identified compounds will aid in the discovery of potential repurposed anti-TB drugs. This study highlights the significance of targeting well known M.tb RNA methyltransferases to combat drug-resistant M.tb and proposes the mentioned drugs as promising inhibitors of GidB for future pre-clinical investigations. Through this multi-step structure-based drug repurposing workflow 4 promising inhibitors of GidB were identified. The identified compounds offer a promising avenue for developing new anti-TB drugs, potentially bolstering the arsenal against drug-resistant strains. Their discovery represents hope for those fighting against the relentless spread of tuberculosis, bringing us closer to more effective treatments for patients in need.