Burke B J, Hopfinger A J
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago 60680.
J Med Chem. 1990 Jan;33(1):274-81. doi: 10.1021/jm00163a045.
Molecular shape and quantitative structure-activity relationship (QSAR) analyses of 52 1-(substituted-benzyl)-imidazole-2(3H)-thione inhibitors of dopamine beta-hydroxylase were carried out. QSARs were developed for sets of 45 and sets of 47 analogues. Molecular shape, as represented by common overlap steric volume and the composite charge density on carbons 3, 4, and 5 of the substituted-benzyl ring are the major inhibition-potency descriptors. Five of the 52 compounds were eliminated prior to analyses on the basis of difficulties in characterizing shape and charge state. Two compounds were outliers. The active conformation deduced in the analyses is a low-energy conformer for both active and inactive inhibitors. This suggests that the intrinsic shape of the molecule due to the selection of X is more important than torsion-angle selection for the bonds between the two rings. The QSARs found in this study have only general similarities to one put forth by Kruse et al. using linear free energy descriptors.
对52种1 -（取代苄基）-咪唑-2（3H）-硫酮多巴胺β-羟化酶抑制剂进行了分子形状和定量构效关系（QSAR）分析。针对45个类似物组和47个类似物组建立了QSAR。由共同重叠空间体积以及取代苄基环上3、4和5位碳的复合电荷密度所表示的分子形状是主要的抑制活性描述符。在分析之前，基于形状和电荷状态表征困难，排除了52种化合物中的5种。有两种化合物为异常值。分析中推导的活性构象对于活性和非活性抑制剂而言都是低能量构象。这表明由于X的选择导致的分子固有形状比两个环之间键的扭转角选择更为重要。本研究中发现的QSAR与Kruse等人使用线性自由能描述符提出的QSAR仅具有一般相似性。
