Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte > MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.

中文翻译：

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哌醋甲酯的构象分析：分子轨道和分子力学方法的比较。

哌醋甲酯（MP）与多巴胺转运蛋白上的可卡因结合位点结合，并抑制多巴胺的再摄取，但似乎没有与可卡因相同的滥用潜力。这项研究是识别可卡因滥用药物的综合努力的一部分，研究了计算技术和溶剂模型的选择对MP和刚性哌醋甲酯（RMP）类似物的构象势能面（PES）的影响，与MP具有相同的多巴胺转运蛋白结合亲和力。构象分析通过AM1和AM1 / SM5.4半经验分子轨道方法，分子力学方法（介电常数等于真空或水的Tripos力场）和HF / 6-31G *分子轨道方法进行在真空阶段。尽管这三种方法在PES的局部细节上有所不同，但是中性和质子化MP的总体趋势是相同的。在真空阶段，质子化在减少局部构象最小值可利用的空间区域方面具有显著作用。溶剂对中性分子的PES影响很小，并且倾向于稳定质子化的物质。发现使用Tripos力场的随机搜索（RS）构象分析技术能够定位使用系统网格搜索通过分子轨道方法找到的最小值。这表明RS / Tripos力场/真空相位协议是定位MP局部最小值的合理选择。但是，与MP和RMP的分子轨道方法相比，Tripos力场提供了更大的苯环旋转势垒。对于中性和质子化情况，这三种方法均发现RMP构象异构体/转化子的苯环旋转势垒（表示为cte，tte和cta）为：cte，tte> MP> cta。溶剂化对RMP的苯环旋转势垒的影响可忽略不计。B3LYP / 6-31G *密度泛函方法用于计算中性MP的苯环旋转势垒，其结果与HF / 6-31G *方法非常相似。