Bogazici University, Department of Chemistry, Bebek, 34342, Istanbul, Turkey.
Michigan State University, Department of Chemistry, East Lansing, Michigan 48824, USA.
Org Biomol Chem. 2023 May 31;21(21):4518-4528. doi: 10.1039/d3ob00162h.
The human topoisomerase IB (hTopoIB) enzyme is a monomeric protein that relaxes the supercoils on double-stranded DNA by forming a covalent DNA/hTopoIB complex by introducing a nick on the DNA strand. Inhibition of hTopoIB results in cell death, which makes this protein a strong target for the treatment of various cancer types, including small-cell lung cancers and ovarian cancers. Camptothecin (CPT) and indenoisoquinoline (IQN) classes of compounds inhibit the hTopoIB activity by intercalating to nicked DNA pairs; however, these inhibitors show different preferences towards DNA bases when bound to the DNA/hTopoIB complex. Here, we investigated the affinities of CPT and one IQN derivative towards different DNA base pairs. The two inhibitors showed different stacking behaviors in the intercalation site and interaction pattern with binding pocket residues, indicating that they have different inhibition mechanisms in the binding pocket that affects the base-pair selectivity. The results obtained from this study are expected to guide researchers in designing gene-specific and more potent compounds to fight cancer through hTopoIB poisoning.
人源拓扑异构酶 IB（hTopoIB）是一种单体蛋白，通过在 DNA 链上引入一个缺口，形成 DNA/hTopoIB 复合物，从而松弛双链 DNA 的超螺旋。抑制 hTopoIB 会导致细胞死亡，这使得该蛋白成为治疗多种癌症类型（包括小细胞肺癌和卵巢癌）的一个强有力的靶点。喜树碱（CPT）和吲噁啉（IQN）类化合物通过嵌入到缺口 DNA 对中来抑制 hTopoIB 的活性；然而，当与 DNA/hTopoIB 复合物结合时，这些抑制剂对 DNA 碱基表现出不同的偏好。在这里，我们研究了 CPT 和一种 IQN 衍生物对不同 DNA 碱基对的亲和力。这两种抑制剂在嵌入部位表现出不同的堆积行为和与结合口袋残基的相互作用模式，表明它们在结合口袋中具有不同的抑制机制，从而影响碱基对的选择性。本研究的结果有望指导研究人员设计针对特定基因的更有效的化合物，通过 hTopoIB 中毒来对抗癌症。
