TRIAGEM VIRTUAL BASEADA EM ESTRTURA PARA A IDENTIFICAÇÃO DE NOVOS POTENCIAIS INIBIDORES DA CASPASE-3

Abstract

In this study, selective inhibitors of caspase-3, an essential apoptotic enzyme and therapeutic target for neurodegenerative diseases, as Alzheimer's disease, were identified. Structure-based virtual screening (SBVS) based on five pharmacophore models derived from a potent in vitro reference inhibitor initially selected over 1000 candidates. After a step of energy minimization in the Pharmit web server, the set was reduced to 123 molecules. Molecular docking analysis further refined the selection to the nine best hits. Among these, molecules 1 (ZINC2691542), 7 (Z6279896683), and 8 (ZINC10050397) showed the most negative binding free energies, suggesting high affinity and inhibitory potentials. Molecular dynamics analysis revealed that hit 8 was the best candidate, exhibiting the lowest RMSD values, indicating low conformational variation and complex stability. RMSF analysis indicated a significant reduction in the flexibility of active site residues, suggesting a tight fit. Additionally, 8 maintained two to four stable hydrogen bonds throughout the simulation, and presented a lower SASA and a constant Rg, demonstrating good structural adaptation. MM/PBSA calculations confirmed the greater energetic stability of 8, with ΔG = –10 kcal.mol⁻¹. In this way, molecules 1, 7, and 8 (with particular emphasis on the latter) are good candidates for future in vitro validation, especially the 8, studies as caspase-3 inhibitors and may become promising prototype compounds for the development of new drugs useful in the treatment of Alzheimer's disease and other neurodegenerative disorders.