Freitas Renato F, Prokopczyk Igor M, Zottis Aderson, Oliva Glaucius, Andricopulo Adriano D, Trevisan Maria Teresa S, Vilegas Wagner, Silva Maria Goretti V, Montanari Carlos A
Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil.
Bioorg Med Chem. 2009 Mar 15;17(6):2476-82. doi: 10.1016/j.bmc.2009.01.079. Epub 2009 Feb 13.
Based on its essential role in the life cycle of Trypanosoma cruzi, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been considered a promising target for the development of novel chemotherapeutic agents for the treatment of Chagas' disease. In the course of our research program to discover novel inhibitors of this trypanosomatid enzyme, we have explored a combination of structure and ligand-based virtual screening techniques as a complementary approach to a biochemical screening of natural products using a standard biochemical assay. Seven natural products, including anacardic acids, flavonoid derivatives, and one glucosylxanthone were identified as novel inhibitors of T. cruzi GAPDH. Promiscuous inhibition induced by nonspecific aggregation has been discarded as specific inhibition was not reversed or affected in all cases in the presence of Triton X-100, demonstrating the ability of the assay to find authentic inhibitors of the enzyme. The structural diversity of this series of promising natural products is of special interest in drug design, and should therefore be useful in future medicinal chemistry efforts aimed at the development of new GAPDH inhibitors having increased potency.
基于其在克氏锥虫生命周期中的关键作用，糖酵解酶甘油醛-3-磷酸脱氢酶（GAPDH）被认为是开发治疗恰加斯病新型化疗药物的一个有前景的靶点。在我们发现这种锥虫酶新型抑制剂的研究项目过程中，我们探索了基于结构和配体的虚拟筛选技术的组合，作为使用标准生化测定法对天然产物进行生化筛选的一种补充方法。七种天然产物，包括腰果酚酸、黄酮类衍生物和一种葡糖基黄酮，被鉴定为克氏锥虫GAPDH的新型抑制剂。非特异性聚集诱导的混杂抑制已被排除，因为在Triton X-100存在的情况下，特异性抑制在所有情况下都没有被逆转或受到影响，这证明了该测定法能够找到该酶的真正抑制剂。这一系列有前景的天然产物的结构多样性在药物设计中具有特殊意义，因此在未来旨在开发具有更高效力的新型GAPDH抑制剂的药物化学研究中应该会很有用。
