Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent
Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent
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DOI：
10.1007/s00894-010-0712-x
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发表时间：
2011-01-01
影响因子：
2.2
通讯作者：
Venanzi, Carol A.
中科院分区：
文献类型：
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作者：
Pandit, Deepangi;Roosma, William;Venanzi, Carol A.
柔性多巴胺再摄取抑制剂的类似物GBR 12909(1)，可能在治疗可卡因滥用方面有潜在的效用。作为这些化合物多巴胺转运体(DAT)/血清素转运体（SERT）选择性的3D-QSAR建模的第一步，我们对1的两种类似物进行了构象分析：哌嗪(2)和相关的哌啶(3)。利用Tripos和MMFF94力场进行随机搜索构象分析，在真空相和隐式溶剂中生成了由分子势能面局部最小值组成的构象群。由于叔胺态氮原子和醚态氧原子类型在电场作用下的不同，在构象群中发现了一些差异。两种力场在描述双苯基部分附近的C(sp(3))-O（sp(3)）键的内部旋转时也存在差异。模型化合物(5)中C-O内旋的HF/6-31G(d)和B3LYP/6-31G(d)水平的分子轨道计算，旨在模拟双苯基邻近对C-O内旋的影响，结果显示-60°至60°之间存在广泛的低能区，在-60°和30°处能量最小，在0°处有低的旋转势垒，与MIMFF94的结果比Tripos的结果更接近。模型化合物(6)的分子力学计算表明，MMFF94力场比Tripos力场对双苯基部分对C-O内旋的影响要敏感得多。
Analogs of the flexible dopamine reuptake inhibitor; GBR 12909 (1), may have potential utility in the treatment of cocaine abuse. As a first step in the 3D-QSAR modeling of the dopamine transporter (DAT)/serotonin transporter (SERT) selectivity of these compounds, we carried out conformational analyses of two analogs of 1: a piperazine (2) and a related piperidine (3). Ensembles of conformers consisting of local minima on the potential energy surface of the molecule were generated in the vacuum phase and in implicit solvent by random search conformational analysis using the Tripos and MMFF94 force fields. Some differences were noted in the conformer populations due to differences in the treatment of the tertiary amine nitrogen and ether oxygen atom types by the force fields. The force fields also differed in their descriptions of internal rotation around the C(sp(3))-O(sp(3)) bond proximal to the bisphenyl moiety. Molecular orbital calculations at the HF/6-31G(d) and B3LYP/6-31G(d) levels of C-O internal rotation in model compound (5), designed to model the effect of the proximity of the bisphenyl group on C-O internal rotation, showed a broad region of low energy between -60 degrees to 60 degrees with minima at both -60 degrees and 30 degrees and a low rotational barrier at 0 degrees, in closer agreement with the MIMFF94 results than the Tripos results. Molecular mechanics calculations on model compound (6) showed that the MMFF94 force field was much more sensitive than the Tripos force field to the effects of the bisphenyl moiety on C-O internal rotation.