Analysis of the in vitro antiviral activity of certain ribonucleosides against parainfluenza virus using a novel computer aided receptor modeling procedure.
Analysis of the in vitro antiviral activity of certain ribonucleosides against parainfluenza virus using a novel computer aided receptor modeling procedure.
复制标题
使用新型计算机辅助受体建模程序分析某些核糖核苷对副流感病毒的体外抗病毒活性。
DOI：
10.1021/jm00124a005
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发表时间：
1989
影响因子：
7.3
通讯作者：
Robins,RK
中科院分区：
文献类型：
--
作者：
Ghose,AK;Crippen,GM;Revankar,GR;McKernan,PA;Smee,DF;Robins,RK
用一种新的计算机辅助受体模拟方法分析了28个核苷类化合物对副流感病毒3型的体外抗病毒活性。该方法涉及我们早期工作的广泛修改（Ghose，A. K.的;克里彭湾MJ Med.Chem.1985，28，333）。它提出了一个更直接的算法的步骤，遭受主观的早期方法。该方法首先确定核苷的可能的低能构象，并为每个分子的每个构象分配优先级值。然后重复执行以下步骤，直到找到可接受的解决方案。从优先级最高的构象开始，将其它分子的各种能量允许构象叠加在其上，根据物理化学性质匹配（或重叠），确定最佳叠加。叠加的分子被分解成最小数量的部分，并且不同区域的局部物理化学性质与它们的结合数据（抗病毒活性）相关。一个修改后的版本的距离几何已被用于几何比较的分子结构。基于28种核糖核苷的病毒评级（VR），该程序假设6-（甲硫基）-9-/3-D-呋喃核糖基嘌呤的最小能量构象作为参考构象，并使用三种物理化学性质，即疏水性、摩尔还原活性和形式电荷密度进行性质匹配。结合位点空腔被划分为七个区域或口袋，以定量区分相互作用的性质。该模型表明，嘌呤环的2-和3-位以及其他环的相应原子具有一定的空间排斥，具有单个五元杂环的核苷将更适合该病毒。甲硫基通过色散相互作用得到强吸引力。亲水基团和分散基团在这里都是有吸引力的。虽然我们的计算支持了先前提出的活性构象利巴韦林，它表明，它不是全球最低能量构象。不同之处在于酰胺基团的取向。由该模型计算的病毒等级与实测值的相关系数为0.971，拟合的解释方差和标准偏差分别为0.880和0.125。基于病毒的复制数据和核苷的化学结构。该模型可用于设计新的抗病毒药物。该模型不仅构成了假设的结合位点空腔的几何形状，而且给出了配体原子与受体相互作用的定量估计。1-3这样的模型对于在缺乏受体和结合位点的明确结构的情况下理解配体-受体相互作用非常有帮助。不仅设计这样一个模型的问题非常复杂4 -7，而且人们还可以质疑从这种有限的信息开发任何物理现实模型的可行性。在这篇介绍中，我们想简要地考虑这种方法的各种问题;在方法部分，将讨论问题的近似解。我们在此采用了我们以前报告中经过大量修改的程序。1-3它是非常普遍的，可以应用于任何类似的问题。
The in vitro antiviral activity of 28 nucleosides against the parainfluenza virus type 3 has been analyzedby using a novel computer aided receptor modeling procedure. The method involves an extensive modification of our earlier work (Ghose, A. K.; Crippen, G. MJ Med. Chem. 1985, 28, 333). It presents a more straightforward algorithm for the steps that suffered from subjectivity in the earlier method. The method first determines the possible low-energy conformations of the nucleosides, and assigns a priority value for each conformation of each molecule. It then performs the following steps repeatedly, until it finds an acceptable solution. Startingfrom the conformation of highest priority, the various energetically allowed conformations of the other molecules sire superimposed on it. On the basis of the physicochemical property matching (or overlapping), the best superposition is determined. The superimposed molecules are dissected into a minimum number of partsand the local physicochemical properties at different regions are correlated with their binding data (antiviral activity). A modified version of distance geometry has been used for geometric comparison of the structure of the molecules. On the basis of the virus rating (VR) of 28 ribonucleosides, this procedure hypothesized the minimum-energy conformation of 6-(methylthio)-9-/3-D-ribofuranosylpurine as a reference conformation and used three physicochemical properties, namely hydrophobicity, molar refractivity, and formal charge density for property matching. The binding-site cavity was divided into seven regions or pockets to differentiate the nature of interaction quantitatively. The model suggests that the 2-and 3-positions of the purine ring and the corresponding atoms of the other ringsget some steric repulsion, and nucleosides having a single five-membered heterocyclic ring will better fit this virus. The methylthio group gets a strong attraction from dispersive interaction. Both hydrophilic and dispersive groups are attractive here. Although our calculation supports the previously suggested activeconformation of ribavirin, it shows that it is not the global minimum-energy conformation. The difference lies in the orientation of the amide group. The calculated viral rating from this model showed a correlation coefficient of 0.971 with the observed values, and the explained variance and the standard deviation of the fit were 0.880 and 0.125, respectively.The objective of this work was to develop a comple-mentary model of the binding site of nucleosides to the parainfluenza virus receptor, based upon the virus inhib-ition data and the chemical structure of the nucleosides. The model could be applied to design novel antiviral agents. The model not only constitutes the geometrical shape of the hypothetical binding site cavity but also gives a quantitative estimation of the interaction of the ligand atoms with the receptor. 1-3 Such a model is very helpful in understanding the ligand-receptor interaction in the absence of the explicit structure of the receptor and the binding site. Not only is the problem of designing such a model very complex4-7 but one can also question the feasibility of developing any physically realistic model from such limited information. In this introduction we want to consider briefly the various problems of the approach; in the Methods section an approximate solution of the problem will be discussed. We haveadopted here an ex-tensively modified procedure from our earlier reports. 1-3 It is very general and can be applied to any comparable problem.