Marine Bastadins as Potent ACAT1 Inhibitors: Integrated Molecular Docking and ADMET Profiling for Anticancer Drug Discovery
DOI:
https://doi.org/10.22399/ijcesen.4378Keywords:
ACAT1, Bastadins, Cancer, Molecular Docking, ADMETAbstract
Acyl-CoA: cholesterol acyltransferase 1 (ACAT1) is a key enzyme in lipid homeostasis, catalyzing the esterification of cholesterol, a process closely associated with the metabolic reprogramming that supports tumor progression. In this study, twenty-two Bastadins, bromotyrosine-derived macrocyclic metabolites isolated from the marine sponge Ianthella basta, were evaluated as potential human ACAT1 inhibitors using molecular docking, ADME analysis, and toxicity predictions. These compounds were selected based on prior reports of their experimental ACAT1 inhibitory activity, underscoring their potential as lead scaffolds for enzyme modulation. Molecular docking was performed using PyRx (v0.8), and ADMET properties were evaluated with ADMETlab 3.0 and ProTox 3.0. Among the compounds, Bastadins 8, 10, 13, and 19 demonstrated the strongest affinities toward ACAT1 (-11.0 to -11.5 kcal/mol). Bastadin 13 exhibited the most stable complex formation (-11.5 kcal/mol), involving strong hydrogen bonds as well as π-π T-shaped and π-alkyl interactions with key residues, including His460 and Phe384. Similarly, Bastadin 19 displayed a high interaction energy (-11.4 kcal/mol), engaging in stable polar and hydrophobic contacts with residues such as His460, Trp420, Asn421, Phe254, and Tyr417. ADMET predictions indicated that both Bastadins 13 and 19 possess favorable pharmacokinetic properties, including enhanced intestinal absorption, metabolic stability, and low predicted toxicity. Overall, these compounds emerge as the most promising ACAT1 inhibitors, combining strong binding, robust interactions with critical residues, and favorable ADMET characteristics, offering a rational framework for the development of novel anticancer agents, and providing a solid basis for further experimental validation and optimization in targeted cancer therapy
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