Pharmacophore mapping of the crucial mediators of dual inhibitor activity of PanK and PyrG in tuberculosis disease

ABSTRACT

Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, responsible for 1.66 million documented deaths in 2020. The increase in reported cases of M. tuberculosis resistance to the main drugs shows the need to develop new and efficient drugs for better TB control. A strategy to overcome the resistance problem could be the polypharmacology approach, whereby researchers develop a single molecule that acts on different targets. Polypharmacology could have features that make it more effective than classical polypharmacy, in which investigators pull various drugs with high affinity for one target together. Based on the effectiveness of multitargeting, this work aimed to use combined in silico techniques to identify potential dual inhibitors for Pantothenate Kinases (PanK) and CTP synthetase PyrG. In silico drug design allows for screening of potential leads, thus decreasing time and resource consumption. This study demonstrates an optimised and proven screening technique to discover a potential small-molecule inhibitor of Mycobacterium tuberculosis PanK and PyrG. The favourable binding free energy values and interaction profiles show ZINC53995076 as a potent dual inhibitor of the Mycobacterium tuberculosis PanK and PyrG.

KEYWORDS:

• Tuberculosis
• PanK
• PyrG
• pharmacophore design
• molecular dynamics simulations

Acknowledgments

The authors acknowledge the College of Health Science, University of KwaZulu-Natal, South Africa, and Centre of High-Performance Computing (CHPC) Cape Town, RSA, for computational resources (www.chpc.ac.za).

Disclosure statement

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

Additional information

Funding

MAE is grateful for the financial support of the National Research Foundation, South Africa (NRF/TWAS) for the awarded Grant No: NRF/TWAS No 110906.