Integrated density functional theory, molecular docking, and pharmacokinetic modeling of mukonal and its derivatives as inhibitors of the Plasmodium falciparum TFIIH complex (Tfb5 subunit).

Plasmodium falciparum is the most dangerous malaria parasite affecting humans. Compounds such as mukonal, 7-hydroxymukonal, and 7-methoxymukonal have shown potential for the treatment of this disease. Density Functional Theory (DFT), molecular docking, and pharmacokinetic analyses are valuable computational approaches for predicting potential drug candidates against P. falciparum. In this study, three compounds mukonal, 7-hydroxymukonal, and 7-methoxymukonal were optimized and evaluated through molecular docking and pharmacokinetic analysis against the target protein PF3D7_1441900 (transcription factor TFIIH complex subunit Tfb5, putative) from P. falciparum isolate 3D7. Frontier molecular orbital and density of states analyses revealed that 7-methoxymukonal has a relatively smaller energy gap compared with the other two compounds. In addition, 7-methoxymukonal exhibited the strongest binding affinity toward the target protein. The ADME results indicated favorable drug-like properties and low toxicity, further supporting the therapeutic potential of these compounds. Overall, our theoretical findings suggest that compound 3, namely 7-methoxymukonal, is the most promising candidate against the selected protein, in agreement with the other computed parameters.