Between Chemical Simplicity and Biological Complexity: In Silico Profiling of Butyrolactones I and III as Potential Multi-Target Drug Candidates

The development of multi-targeted therapeutic agents is increasingly recognized as essential for treating multifactorial diseases. Butyrolactone I and butyrolactone III, γ-butyrolactone derivatives isolated from the marine fungus Aspergillus terreus, represent structurally related natural products with largely unexplored polypharmacological potential. This study employed a comprehensive in silico approach combining ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics simulations to evaluate their therapeutic potential across multiple pharmacological targets. Physicochemical analysis revealed favorable drug-like properties for both compounds, with complete compliance with Lipinski’s Rule of Five, high predicted gastrointestinal absorption (>80%), and acceptable toxicity profiles (toxicity class 4, LD50 = 2000 mg/kg). Neither compound showed hepatotoxic, neurotoxic, cardiotoxic, carcinogenic, or mutagenic liabilities. Frontier molecular orbital analysis (DFT/B3LYP/6-31G(d,p)) revealed comparable HOMO energies (−6.054 and −6.059 eV), with butyrolactone III exhibiting enhanced kinetic stability based on a larger HOMO–LUMO gap (4.662 eV vs. 4.443 eV) and higher chemical hardness (η = 2.331 eV vs. 2.222 eV). Molecular docking against four therapeutic targets revealed target-selective binding profiles: butyrolactone III demonstrated binding affinity toward acetylcholinesterase exceeding donepezil (−9.0 vs. −8.3 kcal/mol), while butyrolactone I exhibited MDM2 binding affinity slightly exceeding nutlin-3a (−7.8 kcal/mol). Both compounds showed moderate interactions with COX-2 and topoisomerase IV. Molecular dynamics simulations validated the stability of AChE complexes (RMSD < 2.0 Å) and the MDM2–butyrolactone I complex (RMSD: 0.69 ± 0.09 Å), while the MDM2–butyrolactone III complex exhibited significant instability (RMSD up to 3.55 Å), highlighting the critical role of the prenyl group in MDM2 recognition. These findings, consistent with, though not a direct experimental validation of, previously published in vitro data, support the evaluation of butyrolactone III as a scaffold for neuroprotective agents and butyrolactone I as a p53 pathway modulator for cancer therapy, illustrating the potential value of fungal metabolites in multi-target drug discovery and the role of integrated computational approaches in prioritizing candidates for subsequent experimental testing.