Jena Nihar R, Mishra Phool C
Department of Physics, Banaras Hindu University, Varanasi, 221005, India.
J Mol Model. 2007 Jan;13(1):267-74. doi: 10.1007/s00894-006-0157-4. Epub 2006 Oct 6.
The enzyme topoisomerase I (topo I), which is essential for cell replication, transiently causes a DNA single strand break and makes a complex with it. The anti-cancer agent camptothecin (CPT) binds to the topo I-DNA complex and stabilizes it, preventing resealing of the broken DNA strand and cell growth. Considering the structural factors of CPT that are believed to be involved in stabilizing the topo I-DNA complex via hydrogen bonding and stacking interactions, designs of two new analogues of CPT (topo I inhibitors) have been suggested. The molecular geometries of CPT, two of its analogues and certain other related molecules included in the study were fully optimized in both gas phase and aqueous media at the B3LYP/6-311++G(d,p) level of density functional theory. Solvation effects of aqueous media were treated using the polarizable continuum model (PCM). Net CHelpG charges and surface molecular electrostatic potentials (MEP) near the atomic sites of the molecules were studied. Structural analogy and surface MEP values suggests that the two new CPT analogues studied here would be potent topoisomerase I inhibitors.
拓扑异构酶I（topo I）是细胞复制所必需的酶，它会暂时导致DNA单链断裂并与之形成复合物。抗癌药物喜树碱（CPT）与topo I-DNA复合物结合并使其稳定，从而阻止断裂的DNA链重新封闭以及细胞生长。考虑到据信通过氢键和堆积相互作用参与稳定topo I-DNA复合物的CPT的结构因素，已提出了两种新的CPT类似物（topo I抑制剂）的设计方案。在密度泛函理论的B3LYP/6-311++G(d,p)水平上，对CPT及其两种类似物以及该研究中包含的某些其他相关分子的分子几何结构在气相和水相中都进行了完全优化。使用极化连续介质模型（PCM）处理水相介质的溶剂化效应。研究了分子原子位点附近的净CHelpG电荷和表面分子静电势（MEP）。结构类比和表面MEP值表明，此处研究的两种新的CPT类似物将是有效的拓扑异构酶I抑制剂。
