Tonmunphean Somsak, Wijitkosoom Atchara, Tantirungrotechai Yuthana
Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand.
Bioorg Med Chem. 2004 May 1;12(9):2005-12. doi: 10.1016/j.bmc.2004.03.003.
Based on the fact that different isomers may exhibit substantial distinct activities, quantum chemical calculations and automated molecular docking simulations were carried out for 13 dispiro-1,2,4,5-tetraoxane compounds, which experimentally exist as a mixture of several isomers, to elucidate the most probable isomer(s) responsible for their antimalarial activity. The results indicate significant effects of stereoisomer on the binding mode and the activity. Moreover, the antimalarial potency of each compound can be described by the docking results. Compounds 1, 2, 4, 5, 7, and 9 have the most probable isomers coordinate suitably with heme iron and hence they have high activities while the most probable isomer in compounds 3 and 8 could not bind appropriately to heme yielding only moderate activities. On the other hand, the steric hindrance in compounds 11-13 prevents an approach of heme iron to peroxide bonds resulting in a devoid of antimalarial activity. However, compounds 6 and 10 with isopropyl substituents exhibit a different docking character, which is possibly caused by a limitation in molecular flexibility of the available docking technique. Our results can be used as a guideline for stereochemical control in synthesis process to improve drug's potency.
基于不同异构体可能表现出显著不同活性这一事实，对13种二螺-1,2,4,5-四氧六环化合物进行了量子化学计算和自动分子对接模拟，这些化合物在实验中以几种异构体的混合物形式存在，以阐明对其抗疟活性负责的最可能的异构体。结果表明立体异构体对结合模式和活性有显著影响。此外，每种化合物的抗疟效力可以通过对接结果来描述。化合物1、2、4、5、7和9具有最可能的异构体，能与血红素铁适当配位，因此它们具有高活性，而化合物3和8中最可能的异构体不能与血红素适当结合，仅产生中等活性。另一方面，化合物11 - 13中的空间位阻阻止了血红素铁接近过氧化物键，导致缺乏抗疟活性。然而，具有异丙基取代基的化合物6和10表现出不同的对接特征，这可能是由可用对接技术的分子灵活性限制所导致的。我们的结果可作为合成过程中立体化学控制的指导，以提高药物的效力。
