Repurposing FDA-approved drugs as multi-stage antimalarials: An in silico investigation
Afolayan Funmilayo I D, Adewoyin H. Ademola, Ridwan Abiodun Salaam, Adetula Samson O, Mikhail B J · In Silico Research in Biomedicine · 2026
The emergence of drug-resistant plasmodium parasites is a significant threat to malaria control and elimination programs globally. This has necessitated the need to discover novel and effective drugs to combat the deadly pathogen. Consequently, this study employs Bioinformatics and Chemoinformatics approaches to investigate 1,900 FDA-approved drugs, sourced from the DrugBank database. The molecular docking technique was employed to assess the binding affinity of various FDA-approved drugs with mefloquine, amodiaquine, artemether, and artesunate as controls for benchmarking. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions using various parameters were also conducted using AdmetLab 3.0 algorithm. Furthermore, molecular dynamics simulation and Molecular mechanics-generally-born surface area (MMGBSA) analysis, using GROMACS 2023.3 software, was performed to understand the stability and mechanism of interactions for the promising protein-ligand complexes. The molecular docking analysis identified seven drugs with lower binding affinities, ranging from -11.5 kcal/mol to -8.5 kcal/mol, compared to the controls, which had binding affinities of -9.3 kcal/mol to -7.8 Kcal/mol. However, molecular visualizations of the complexes identified Tepotinib/ Pf PK7, Belumosudil/ Pf s25, Bexarotene/ Pf s230, and Avapritinib/ Pf CDPK4 as promising antimalarial complexes. Molecular dynamics simulation revealed that Belumosudil/ Pf s25, Bexarotene/ Pf s230, and Avapritinib/ Pf CDPK4 have better stability due to prolonged interactions between their respective ligands and key amino acid residues in the binding pockets than Tepotinib/ Pf PK7 complex. Additionally, MMGBSA analysis showed a strong binding affinity for each complex with MMGBSA ΔG bind ranging from -90 kcal/mol to -36 kcal/mol. Meanwhile, ADMET analysis indicates that they have relatively good absorption, metabolism, excretion, oral bioavailability, and distribution properties, albeit with a need for dosage assessment. Hence, this investigation suggests that the identified FDA-approved drugs may be repurposed as novel and effective antimalarial agents. Consequently, they are recommended for further in vivo and in vitro assessments.