Computational screening of natural MtbDXR inhibitors for novel anti-tuberculosis compound discovery

Abstract

DXR (1-deoxy-d-xylulose-5-phosphate reductoisomerase) is an essential enzyme in the Methylerythritol 4-phosphate (MEP) pathway, which is used by M. tuberculosis and a few other pathogens. This essential enzyme in the isoprenoid synthesis pathway has been previously reported as an important target for antibiotic drug design. However, till now, there is no record of any drug-like safe molecule to inhibit MtbDXR. Numerous plant species have been traditionally used for tuberculosis therapies. In this study, we selected six plant species with anti-tubercular properties. The chemoinformatic screening was performed on 352 phytochemicals from those plants against the MtbDXR protein. After molecular docking analysis, we filtered the top five compounds, CID: 5280443 (Apigenin), CID: 3220 (Emodin), CID: 5280863 (Kaempferol), CID: 5280445 (Luteolin), and CID: 6101979 (beta-Hydroxychalcone), based on binding affinity. Molecular dynamics simulations disclosed the stability of the compounds at the active site of the proteins. Finally, in silico ADME and toxicity evaluations confirmed the compounds to be effective and safe for oral administration. Thus, our findings identified three drug-like safe molecules- Apigenin, Kaempferol, and beta-Hydroxychalcone, that showed good stability in the protein’s active site. The results of this computational approach may act as an initial instruction for future in vitro and in vivo testing to identify natural drug-like compounds to treat tuberculosis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti-tuberculosis
• MEP pathway
• MtbDXR
• pharmacoinformatics
• molecular docking
• MD simulation

Acknowledgment

The authors are grateful to K. M. Salim Andalib and Rahat Alam for sharing their knowledge with us while conducting our research. We also appreciate the technical assistance from the Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre; http://www.biosolcentre.org), Jashore 7408, Bangladesh.

Author’s contribution

The experiment was developed, planned, and executed by SI. All data analysis and visualizations are the sole responsibility of SI. With support from RS and AA, SI drafted the manuscript. RS and AA gave the manuscript a rigorous review. AA supervised the project. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

1 https://pubchem.ncbi.nlm.nih.gov

2 http://www.swissadme.ch

Additional information

Funding

The National Science and Technology (NST) Ministry, Bangladesh, supported the research reported in this paper.