Artemisinin derivatives as potential drug candidates against Mycobacterium tuberculosis: insights from molecular docking, MD simulations, PCA, MM/GBSA and ADMET analysis

ABSTRACT

Tuberculosis, one of the most ancient and formidable infectious diseases, primarily arises from the pathogenic bacterium Mycobacterium tuberculosis (Mtb). Phosphoenolpyruvate carboxykinase (Pck), a potential drug target, is essential for the growth of Mtb that involves in the pathway of gluconeogenesis at the centre of phosphoenolpyruvate-pyruvate-oxaloacetate node. This study aims to understand drug-like properties of the compounds derived from artemisinin, and to investigate their inhibitory roles against Mtb. Molecular docking was performed on a set of 56 artemisinin compounds to identify their binding efficacy to the Mtb protein target. Subsequently, the selected top three complexes were subjected to molecular dynamics simulations. By the trajectory analysis, root mean square deviation and radius of gyration indicated the compactness of the systems without much fluctuation. The principal component analysis revealed that the complexes were less dynamic and energetically more favourable, and Gibbs energy landscape revealed the favourable energetic transitions between conformations. The artemisinin dimer primary alcohol holding good bioavailability scores appears highly stable in complex with Pck (MM/GBSA of −37.67 kcal/mol) that stands as a potential inhibitor of the Mtb target. However, further preclinical experiments and investigations are necessary to evaluate the intrinsic properties and to confirm effectiveness of the drug candidate.

KEYWORDS:

• Artemisinin derivatives
• mycobacterium tuberculosis
• protein-drug interactions
• principal component analysis
• binding free energy

Acknowledgements

Author R. Maharjan would like to acknowledge the University Grants Commission, Bhaktapur, Nepal, for the Ph.D. Fellowship (PhD-79/80-S&T-19).

Authors’ contributions

Rajesh Maharjan: Conceived and designed the study, performed data analysis, prepared the figures, and wrote the manuscript; Kalpana Gyawali: Critical feedback and revised the manuscript; Arjun Acharya: Technical support, data analysis, critical feedback and revised the manuscript; Madan Khanal: Critical feedback and revised the manuscript; Madhav Prasad Ghimire: Technical support, critical feedback and revised the manuscript; Tika Ram Lamichhane: Technical support, critical feedback, data analysis and revised the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data supporting the findings of this study are available within the article and its supplementary materials.

Additional information

Funding

This work was supported by University Grants Commission- Nepal [grant number Ph.D. Fellowship (PhD-79/80-S&T-19)].