An In-Silico Investigation on the Molecular Interactions between Ellagic Acid and PfDHFR-TS

Abstract

Ellagic acid (EA) is an antiplasmodial polyphenol with reported in-vitro activity against Plasmodium falciparum. Studies have reported that EA acts in the late erythrocytic stages of P. falciparum (Pf) when DNA synthesis is taking place. Pf dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important enzyme for DNA synthesis as its inhibition can kill the parasite. As there is no reported study on the molecular interactions between EA and PfDHFR-TS, we aim to study the molecular interactions between EA and PfDHFR-TS (PDB ID: 3DGA) through molecular docking, molecular dynamics (MD) simulations, binding free energy (MM-GBSA) calculations, and density functional theory (DFT) studies. Site-specific and blind docking revealed that EA has a high binding affinity for the active site of PfDHFR-TS. EA formed hydrogen bonds with multiple active site residues. MD simulations for 100 ns revealed that the PfDHFR-TS-EA complex was stable. The average binding free energy of the PfDHFR-TS-EA complex throughout the 100 ns MD simulations was −39.84 kcal/mol. The energy difference (ΔE = 0.04089 eV) obtained from DFT studies indicates the electrical stability and reactivity of EA at the active site of PfDHFR-TS. We conclude that the antiplasmodial activity of EA might be attributed to its ability to potentially bind with PfDHFR-TS.

Graphical Abstract

Keywords:

• Molecular docking
• MD simulation
• MM-GBSA
• ellagic acid
• PfDHFR-TS

Acknowledgments

James H. Zothantluanga is thankful to the University Grants Commission and the Ministry of Tribal Affairs, Government of India for providing the UGC-SRF fellowship (Award No: 202122-NFST-MIZ-03095) to support his Ph.D. research project.

Author contributions

Study design: JHZ; Software, analysis, result interpretation: JHZ, AKU, MR; Drafting, figures, and editing: JHZ, WAE, LP, MSB, DT; Supervision, and critical review: AKU, MR

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

All the data will be made available upon proper request to the corresponding author.