# Structure-Based Screening of Deep-Sea Microbial Metabolites Against Plasmodium falciparum Dihydroorotate Dehydrogenase

## TL;DR

This study explores deep-sea microbial compounds as potential new antimalarial drugs by screening their ability to block a key malaria parasite protein.

## Contribution

The study introduces a computational pipeline to identify deep-sea microbial metabolites as novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.

## Key findings

- Five deep-sea compounds showed strong binding to PfDHODH with higher Glide scores than Primaquine.
- MD simulations confirmed stable protein-ligand interactions for top hits like (±)-puniceusine P and 15-O-methyl ML-236A.
- ADME profiling indicated favorable drug-like properties for the selected compounds.

## Abstract

Malaria remains a serious global health problem, partly because the parasite that causes the disease is becoming resistant to existing medicines. Thus, to address this challenge, the present study explores whether natural chemical substances from marine microorganisms could serve as starting points for new antimalarial drugs. These deep-sea organisms survive under extreme conditions and often produce unusual chemical structures that may interact with disease-causing proteins in new ways. Using advanced computer-based methods, we screened a large collection of deep-sea microbial compounds to identify those most likely to block a protein that the malaria parasite needs to survive. Several compounds showed strong and stable interactions with this protein and displayed properties consistent with drug-like behavior. Computer simulations further suggest that these compounds remain stably bound over time, supporting their potential effectiveness. Although laboratory testing is still required, our findings highlight deep-sea microbial compounds as promising candidates for future antimalarial drug development. This research may contribute to the long-term goal of discovering safer and more effective treatments for malaria.

Malaria is a major global health concern caused by Plasmodium parasites, among which Plasmodium falciparum is responsible for the most severe and fatal cases. The emergence of drug resistance to existing antimalarial therapies necessitates the discovery of novel molecular targets and chemically distinct inhibitors. Current study employed an integrated in silico drug discovery pipeline combining high-throughput structure-based virtual screening of 1549 deep-sea marine microbial metabolites with MM-GBSA binding free-energy estimation, QikProp-based ADME/Tox profiling, and 100 ns molecular dynamics (MD) simulations to link rapid screening with dynamic verification of binding stability. Molecular docking against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH; PDB ID: 7KZ4) yielded five top-ranked compounds with Glide scores ranging from −12.02 to −10.61 kcal·mol−1, which is higher than the Primaquine (−6.920 kcal·mol−1; a clinically approved antimalarial reference compound). MM-GBSA analysis further refined hit selection, producing binding free energies (ΔG_bind) between −63.28 and −31.37 kcal·mol−1. The selected lead compounds included (±)-puniceusine P, aspergilol F, tersaphilone C, 4-carbglyceryl-3,3′-dihydroxy-5,5′-dimethyldiphenyl ether, and 15-O-methyl ML-236A. The top hits were subjected to 100 ns MD simulations in Desmond, demonstrating stable protein–ligand complexes, particularly for (±)-puniceusine P and 15-O-methyl ML-236A (protein backbone root mean square deviation (RMSD; ~0.8–1.0 Å). ADME profiling indicated acceptable predicted physicochemical and pharmacokinetic properties. Overall, these in silico findings highlight deep-sea marine microbial metabolites as promising PfDHODH inhibitor candidates requiring experimental validation.