Submacular and Intraretinal Fluid Associated with Arteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND

Malaria is a major global health issue, which significantly affects developing countries, including Indonesia. Plasmodium falciparum, the leading cause of malaria mortality, is increasingly resistant to standard treatments. The antimalarial properties of compounds derived from Streptomyces sp. have been demonstrated in several in vivo and in vitro studies, although their exact mechanism of action remains unclear. This study explores Streptomyces sp. metabolites as potential antimalarials targeting PfDHODH and PfDPCK, essential enzymes for P. falciparum survival.

METHODS

A comprehensive in silico screening was employed, including phylogenetic analysis of PfDHODH and PfDPCK, network protein analysis, identification and preparation of Streptomyces sp. bioactive compounds, structural preparation of target enzymes, molecular docking and visualization, antimalarial efficacy prediction, assessment of drug-likeness and toxicity, and molecular dynamics simulations.

RESULTS

Phylogenetic analysis confirmed that PfDHODH and PfDPCK are distinct from human proteins, reducing off-target risks. Network analysis identified nine proteins linked to PfDHODH and one for PfDPCK. From 27 Streptomyces sp. bioactive compounds, caboxamycin, bisanhydroaklavinone, napyradiomycin A1, and gardenomycin A showed the strongest binding to target enzymes. These compounds occupied the active sites of PfDHODH and PfDPCK, mirroring control ligands (FMN, Opera1). PASS analysis indicated strong antiprotozoal potential for bisanhydroaklavinone and gardenomycin A. Toxicity analysis revealed bisanhydroaklavinone's mutagenicity and carcinogenicity risks, while napyradiomycin A1 showed moderate hepatotoxicity. Nonetheless, molecular dynamics confirmed stable interactions, highlighting their promise as antimalarial candidates. However, their toxicity profiles warrant further investigation to ensure safe therapeutic application.

CONCLUSION

PfDHODH and PfDPCK were identified as selective targets in P. falciparum. Four Streptomyces-derived compounds showed strong binding, stability, and promising antimalarial potential with acceptable predicted toxicity, warranting further evaluation. However, only caboxamycin and gardenomycin show potential for antimalarial drug development, with acceptable predicted toxicity profiles, making them suitable candidates for in vitro and in vivo testing prior to clinical evaluation.