Balogh Balazs, Carbone Anna, Spanò Virginia, Montalbano Alessandra, Barraja Paola, Cascioferro Stella, Diana Patrizia, Parrino Barbara
Department of Organic Chemistry, Semmelweis University, Hogyes E. u. 7, H-1092 Budapest, Hungary.
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy.
Curr Comput Aided Drug Des. 2017;13(3):208-221. doi: 10.2174/1573409913666170124100334.
Isoindolo[2,1-a]quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning.
Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-a]quinoxalin-6-imines, by comparing them with known inhibitors.
Different X-ray crystallographic structures with co-crystallized inhibitors were investigated and their binding modes were analyzed. The structures of the inhibitors were also compared through a pharmacophore analysis. As a validation of our docking method, the co-crystallized inhibitors were re-docked.
Our docking studies performed on Isoindolo[2,1-a]quinoxalines and other inhibitors revealed very important common features responsible for topoisomerase I inhibition that can improve the design of new inhibitors.
异吲哚并[2,1-a]喹喔啉类化合物是一类重要的化合物，对不同的人类肿瘤细胞系表现出强大的抗增殖活性，且为拓扑异构酶I抑制剂。特别是，最近合成的它们的水溶性亚胺或亚胺鎓盐对NCI-60肿瘤细胞系面板显示出强大的生长抑制作用，对最具活性的化合物进行的生物学研究表明，它们通过拓扑异构酶I中毒导致DNA损伤。
在此，我们通过分子建模方法，将水溶性异吲哚并[2,1-a]喹喔啉-6-亚胺与已知抑制剂进行比较，研究其抑制拓扑异构酶I的共同特征。
研究了与共结晶抑制剂的不同X射线晶体结构，并分析了它们的结合模式。还通过药效团分析比较了抑制剂的结构。作为对我们对接方法的验证，对共结晶抑制剂进行了重新对接。
我们对异吲哚并[2,1-a]喹喔啉类化合物和其他抑制剂进行的对接研究揭示了抑制拓扑异构酶I的非常重要的共同特征，这可以改进新抑制剂的设计。
