Flavonoids and Alkaloids from Murraya paniculata Exhibit Potential as DDI1 Inhibitors in Plasmodium falciparum: A Molecular Docking Analysis

Abstract

Background: The emergence of drug-resistant Plasmodium falciparum strains has created an urgent need for new malarial therapeutic targets. The DNA Damage-Inducible Protein 1 (DDI1), which plays a critical role in protein degradation and parasite survival, has been identified as a promising molecular target for antimalarial drug development. Murraya paniculata, a plant rich in alkaloids, flavonoids, and tannins, has shown antimicrobial and antiparasitic properties, but its interaction with DDI1 remains unexplored. Objective: This study aimed to evaluate the binding potential, pharmacokinetics, and toxicity of M. paniculata phytoconstituents as DDI1 inhibitors using the crystal structure with Protein Data Bank code 2i1a. Methods: Representative alkaloid, flavonoid, and tannin compounds from M. paniculata were retrieved from PubChem, converted to 3D structures, and energy-minimized. The 3D structure of DDI1 (PDB ID: 2i1a) was obtained from the RCSB Protein Data Bank. Molecular docking was performed using Molegro Virtual Docker, while SwissADME and ProTox-II were used to assess pharmacokinetics and toxicity. Results: Alkaloid depicted the strongest binding affinity (-7.2 kcal/mol), forming key hydrogen bonds with Tyr205 and Lys325 at the DDI1 active site, followed by flavonoid (-6.9 kcal/mol) and tannin (-4.2 kcal/mol). Most compounds demonstrated favorable GI absorption and complied with Lipinski’s rule of five. Toxicity predictions indicated low acute toxicity (Class IV, LD50: 1190 mg/kg) with potential hepatotoxicity. Conclusion: M. paniculata alkaloids and flavonoids tannins have promising potential as DDI1 (PDB ID: 2i1a) inhibitors, supporting their development as lead structures for novel antimalarial agents.