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

Abstract

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

Keywords:

• Drug repurposing
• flavin-dependent thymidylate synthase
• methyltransferases
• molecular dynamics

Acknowledgements

Sana Tanweer acknowledges a Senior Research Fellowship from the Indian Council of Medical Research (ICMR), India. Salma Jamal acknowledges a Young Scientist Fellowship from the Department of Health Research (DHR), India. Abhinav Grover and Sonam Grover are grateful to University Grants Commission, India for the Faculty Recharge Position. Sonam Grover is grateful to Jamia Hamdard for DST Purse grant and UGC start up grant (F.4-5/2018(FRP-Start-Up-Grant) (Cycle IV) (BSR).

Author contributions

SJ conceived and designed the experiments. ST, SJ and SM performed. SJ, ST, NS, FA and F analyzed the data. All authors contributed to the writing of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.