Oplodiol and nitidine as potential inhibitors of Plasmodium falciparum dihydrofolate reductase: insights from a computational study

Abstract

Many natural products have been shown to possess antiplasmodial activities, but their protein targets are unknown. This work employed molecular docking and molecular dynamics simulations to explore the inhibitory activity of some antiplasmodial natural products against wild-type and mutant strains of Plasmodium falciparum dihydrofolate reductase (PfDHFR). From the molecular docking study, 6 ligands preferentially bind at the active site of the DHFR domain with binding energies ranging from −6.4 to −9.5 kcal/mol. Interactions of compounds with MET55 and PHE58 were mostly observed in the molecular docking study. From the molecular dynamics study, the binding of 2 of the ligands—nitidine and oplodiol—was observed to be stable against all tested strains of PfDHFR. The average binding free energy of oplodiol in complex with the various PfDHFR strains was −93.701 kJ/mol whereas that of nitidine was −106.206 kJ/mol. The impressive in silico activities of the 2 compounds suggest they could be considered for development as potential antifolate agents.

Communicated by Ramaswamy H. Sarma

Molecular docking and molecular dynamics simulation studies suggest oplodiol and nitidine as compounds capable of inhibiting Plasmodium falciparum dihydrofolate reductase and its variants.

Keywords:

• Biophysics
• enzymes
• malaria
• molecular docking
• molecular dynamics simulations

Acknowledgment

The authors express their gratitude to the Center for High Performance Computing, Cape Town, South Africa for the generous access to the Lengau cluster for the MD simulations. The authors are also grateful to Mr. Aaron Boakye and Mr. Prince Manu for their assistance in making some of the figures.

Author contributions

LSB, ENG and LA conceived the study. All experiments were designed by LSB, ENG, LA and JOM. Computations were made by LA, ENG and JOM. Data analysis was done by LA, ENG, JOM and LSB. The manuscript was prepared by LA, ENG, JOM and LSB. All authors read and approved the final manuscript.

Data availability statement

All data generated or analyzed during this study are included in this published article and the associated Supplementary Materials.

Disclosure statement

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Funding

Authors received no direct funding for this study.