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

2023; Taylor & Francis; Volume: 44; Issue: 6 Linguagem: Inglês

10.1080/10406638.2023.2244633

1563-5333

James H. Zothantluanga, Abd. Kakhar Umar, Wafa Ali Eltayb, Lima Patowary, Malita Sarma Borthakur, Dubom Tayeng, Dipak Chetia,

Computational Drug Discovery Methods

AbstractEllagic 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.Keywords: Molecular dockingMD simulationMM-GBSAellagic acidPfDHFR-TS AcknowledgmentsJames 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 contributionsStudy design: JHZ; Software, analysis, result interpretation: JHZ, AKU, MR; Drafting, figures, and editing: JHZ, WAE, LP, MSB, DT; Supervision, and critical review: AKU, MRDisclosure statementNo potential conflict of interest was reported by the authors.Data availability statementAll the data will be made available upon proper request to the corresponding author.