Department of Chemistry and Biochemistry and the Warren Center for Drug Discovery, University of Notre Dame, Notre Dame, IN 46556-5670, USA.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
ChemMedChem. 2023 Oct 4;18(19):e202300292. doi: 10.1002/cmdc.202300292. Epub 2023 Aug 10.
Through an understanding of the conformational preferences of the polyketide natural product (-)-zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a set of three structural handles for further structure-activity relationship (SAR) studies of this potent microtubule-stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.
通过了解聚酮天然产物（-）-zampanolide 的构象偏好，以及控制这些偏好的结构基序，我们开发了一种线性 zampanolide 类似物，对癌细胞系表现出很强的细胞毒性。这一发现为进一步研究这种强效微管稳定剂的构效关系（SAR）提供了一组三个结构处理。此外，它还提供了配体预组织、构象灵活性和生物效力之间复杂关系的更多证据。与药物化学的传统观念相反，这些结果表明，整体构象灵活性的增加不一定对蛋白质结合亲和力和生物活性有害。
