Multifaceted role of drugs: a potential weapon to outsmart Mycobacterium tuberculosis resistance by targeting its essential ThyX.

Tuberculosis (TB) is one of the prominent cause of deaths across the world and multidrug-resistant and extensively drug-resistant TB continues to pose challenges for clinicians and public health centers. The risk of death is extremely high in individuals who have compromised immune systems, HIV infection, or diabetes. Research institutes and pharmaceutical companies have been working on repurposing existing drugs as effective therapeutic options against TB. The identification of suitable drugs with multi-target affinity profiles is a widely accepted way to combat the development of resistance. Flavin-dependent thymidylate synthase (FDTS), known as ThyX, is in the class of methyltransferases and is a possible target in the discovery of novel anti-TB drugs. In this study, we aimed to repurpose existing drugs approved by Food and Drug Administration (FDA) that could be used in the treatment of TB. An integrated screening was performed based on computational procedures: high-throughput molecular docking techniques, followed by molecular dynamics simulations of the target enzyme, ThyX. After performing in silico screening using a library of 3,967 FDA-approved drugs, the two highest-scoring drugs, Carglumic acid and Mesalazine, were selected as potential candidates that could be repurposed to treat TB.Communicated by Ramaswamy H. Sarma.