Multi-target molecular dynamic simulations reveal glutathione-S-transferase as the most favorable drug target of knipholone in Plasmodium falciparum

Abstract

Knipholone is an antiplasmodial phytocompound obtained from the roots of Kniphofia foliosa. Despite several available studies, the molecular drug targets of knipholone in P. falciparum remained unknown. Nowadays, in silico techniques are widely used to study the molecular interactions between compounds and proteins as they provide results quickly with high precision and accuracy. In this study, we aim to identify the potential molecular drug targets of knipholone in P. falciparum. We selected 10 proteins of P. falciparum with unique metabolic functions and we found that knipholone showed better binding affinity than the native ligands of 6 proteins. Out of the 6 proteins, knipholone showed better enzyme inhibitory potential than the native ligands of 4 proteins. We carried out a 100 ns MD simulations for knipholone and the native ligands of four proteins and this was followed by binding free energy calculations. In each step, the performance of knipholone was compared to the native ligands of the proteins. Knipholone outperformed the native ligand of Glutathione-S-Transferase (1OKT) at crucial computational studies as evidence from the lower protein–ligand root mean square deviation value, protein root mean square fluctuation value, and protein–ligand binding free energies. The ligand properties of knipholone provide additional evidence for its stability and it maintains adequate protein–ligand contacts during the entire simulation. The density functional theory study also supported the stability of knipholone at the active binding site of 1OKT. From the studied proteins, we conclude that Glutathione-S-Transferase is the most favorable drug target for knipholone in P. falciparum.

Communicated by Ramaswamy H. Sarma

Keywords:

• Plasmodium falciparum
• knipholone
• in silico
• molecular dynamics
• molecular mechanism
• drug targets
• density functional theory

Acknowledgement

James H. Zothantluanga gratefully acknowledges the University Grant Commission and the Ministry of Tribal Affairs, Government of India for providing a UGC-SRF fellowship (Award No.: 202122-NFST-MIZ-03095) to support his Ph.D. research project. This study was also supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2023R96), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Authors’ contribution

Study design: MS, JHZ, DC; Software: MS, MA, FAT, TNA, STA; Figures: MA, FAT, TNA, STA; Data analysis: MS, JHZ, DC; Drafting: MS, JHZ; Critical review and supervision: JHZ.

Data availability statement

Any data will be made available upon reasonable request to the corresponding author.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

The authors did not receive any funds for the study.