RESUMO
Molecular interaction field, density functional, and docking studies of novel potential ferrocene inhibitors of HIV-1 integrase (IN) are reported. The high docking scores, analysis of the ligand-receptor interactions in the active site as well as the molecular interaction potential calculations at the binding site of the receptor indicate important features for novel HIV-1 IN inhibitors. We also confirm in this work a novel binding trench in HIV-1 integrase, recently reported in a theoretical work by other authors. This observation may be interesting since the lack of detailed structural information about IN-ligand interactions has hampered the design of IN inhibitors. Our proposed ligands are open to experimental synthesis and testing.
Assuntos
Desenho de Fármacos , Compostos Ferrosos/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Ácidos/química , Sítios de Ligação , Integrase de HIV/química , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Metalocenos , Modelos Moleculares , Estrutura Terciária de ProteínaRESUMO
This article describes the synthesis and inhibitory activities of a series of new 3-piperonylcoumarins, designed as inhibitors of glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from Trypanosoma cruzi. The design was based on the structures of previously identified natural products hits. The most active synthesized derivatives contain heterocyclic rings at position 6. SAR studies, performed by electronic indices methodology (EIM), clustered the molecules in different groups due to the chemical substitutions regarding the biological activity. Molecular modeling studies by docking suggested a different binding mode for the most active derivatives, when compared to natural hit chalepin. Moreover, the coumarin ring seems to act only as a spacer group.
