Mapeamento de Interações Intermoleculares de Inibidores de Segunda Geração da mTOR: Evidências Computacionais para o Desenho de Novos Ligantes

Resumo

Second-generation mTOR inhibitors have been widely explored for their potential to overcome selectivity and efficacy limitations of earlier drugs. In this study, we performed a comprehensive mapping of intermolecular interactions between 59 ATP-competitive mTOR inhibitors and the kinase active site using molecular docking. The analysis revealed conserved anchoring features, particularly hydrogen bonds involving the hinge region (Val2240 and surrounding residues) and hydrophobic contacts distributed along the ATP pocket. Distinct structural classes including purine, pyrimidine, and morpholine containing scaffolds exhibited characteristic interaction patterns that correlated with experimental IC₅₀ trends. Compounds bearing dual hinge-binding motifs showed the most favorable docking energies and interaction consistency. Based on the most recurrent and stabilizing contacts, we proposed new ligand designs incorporating optimized aromatic cores, enhanced hydrogen-bond donors/acceptors, and tailored substituents for improved occupancy of hydrophobic subpockets. These findings provide computational evidence supporting structure-based strategies for developing next-generation mTOR inhibitors with enhanced affinity and interaction specificity. Overall, the study confirms key determinants of ligand recognition and offers a rational foundation for future medicinal chemistry optimization.