Structure-Based Docking and Interaction Analysis of Indonesian Phytochemicals Targeting SAP2 (1EAG) for Antifungal Drug Discovery

Abstract

Aims: To evaluate the inhibitory potential of twenty Indonesian phytochemicals against Candida albicans Secreted Aspartic Protease 2 (SAP2; PDB ID: 1EAG) with the biological rationale of inhibiting SAP2-mediated virulence in C. albicans, as this enzyme is essential for fungal tissue invasion and pathogenicity. Study Design: An in silico, structure-based molecular docking study employing a validated flexible-pocket docking model focused on the catalytic Asp32–Asp218 dyad of SAP2. Place and Duration of Study: Computational analyses were performed at the Department of Physics Education, Universitas Kristen Indonesia, Jakarta, between January and October 2025. Methodology: Twenty phytochemicals from Indonesian medicinal plants were prepared using ADFRsuite 1.0 and docked to SAP2 using AutoDock Vina (version 1.2.3). Each ligand underwent five independent docking replicates using a flexible-pocket model encompassing the catalytic and anchoring residues (Asp32, Asp218, Ser282, Leu297, Arg312). Binding free energies (ΔG, kcal mol⁻¹) were evaluated, and protein–ligand interactions were visualized using PyMOL and BIOVIA Discovery Studio Visualizer to identify hydrogen bonds and hydrophobic contacts. Results: All ligands exhibited reproducible binding profiles (SD ≤ 0.25 kcal mol⁻¹), with ΔG values ranging from −4.1 to −6.0 kcal mol⁻¹. Demethoxycurcumin (−5.98 ± 0.04 kcal mol⁻¹), curcumin (−5.90 ± 0.06 kcal mol⁻¹), and bisdemethoxycurcumin (−5.60 ± 0.06 kcal mol⁻¹) showed the strongest affinities through hydrogen bonds with Ser282, Glu278, and Arg312 near the catalytic dyad. Sesquiterpenoids such as germacrone and β-bisabolene bound stably through compact hydrophobic interactions, while smaller ligands like 6-shogaol and citral localized in a peripheral sub-pocket, suggesting a potential allosteric site. Conclusion: Curcuma-derived curcuminoids and Zingiber-derived terpenoids are promising natural SAP2 inhibitors. The flexible-pocket docking strategy enhances reproducibility and establishes a robust computational foundation for subsequent molecular dynamics and in vitro antifungal validation. These findings highlight the potential of identified compounds for lead optimization in future antifungal drug development.