Produção Nacional
Revisado por pares
Discovery of structurally diverse HIV-1 integrase inhibitors based on a chalcone pharmacophore
2007; Elsevier BV; Volume: 15; Issue: 14 Linguagem: Inglês
10.1016/j.bmc.2007.04.041
ISSN1464-3391
AutoresJinxia Deng, Tino W. Sanchez, Laith Q. Al‐Mawsawi, Raveendra Dayam, Rosendo Augusto Yunes, Antonio Garofalo, Michael B. Bolger, Nouri Neamati,
Tópico(s)Click Chemistry and Applications
ResumoRecently, we reported small-molecule chalcones as a novel class of HIV-1 integrase (IN) inhibitors. The most potent compound showed an IC50 value of 2 μM for both IN-mediated 3′-processing and strand transfer reactions. To further utilize the chalcones, we developed pharmacophore models to identify chemical signatures important for biological activity. The derived models were validated with a collection of published inhibitors, and then were applied to screen a subset of our small molecule database. We tested 71 compounds in an in vitro assay specific for IN enzymatic activity. Forty-four compounds showed inhibitory potency <100 μM, and four of them exhibited IC50 values <10 μM. One compound, 62, with an IC50 value of 0.6 μM, displayed better potency than the original chalcone 2 against the strand transfer process. This study demonstrates the systematic use of pharmacophore technologies to discover novel structurally diverse inhibitors based on lead molecules that would exhibit poor characteristics in vivo. The identified compounds have the potential to exhibit favorable pharmacokinetic and pharmacodynamic profiles.
Referência(s)