Use of physicochemical parameters in distance geometry and related three-dimensional quantitative structure-activity relationships: a demonstration using Escherichia coli dihydrofolate reductase inhibitors.
Use of physicochemical parameters in distance geometry and related three-dimensional quantitative structure-activity relationships: a demonstration using Escherichia coli dihydrofolate reductase inhibitors.
复制标题
物理化学参数在距离几何和相关三维定量构效关系中的应用：使用大肠杆菌二氢叶酸还原酶抑制剂的演示。
DOI：
10.1021/jm00381a013
复制
发表时间：
1985
影响因子：
7.3
通讯作者：
Crippen,GM
中科院分区：
文献类型：
--
作者：
Ghose,AK;Crippen,GM
MethodsThe方法在本工作中遵循的是类似的，在我们早期的工作4中所描述的，除了使用的配体原子的物理化学参数相关的网站口袋他们的相互作用。该方法的简要描述如下：（i）构造满足晶体学键长和键角的每个配体分子，（ii）在活性构象假设的基础上构造相对于配体分子的一些位点口袋。可以假定活性构象的一些或全部原子占据位点口袋以提供其相互作用。换句话说，这些原子是代表的网站口袋（见参考文献4的详细解释），（iii）评估几何允许的结合模式。术语结合模式是指配体的哪个原子进入哪个位点口袋。由于围绕各种二面角的内部旋转以及配体相对于受体的刚性旋转和平移，大量几何上可行的结合模式是可能的，除非这种运动受到受体位点的空间要求的限制。（iv）当配体的一个原子（或多个原子）进入位点口袋时，它与位点相互作用，并且相互作用能是原子的一个或多个物理化学参数的函数。假设相互作用为线性函数，则特定结合模式的结合能可以由下式给出：
MethodsThe method followed in the present work is similar to that described in our earlier work4 except for using physicochemical parameters of the ligand atoms to cor-relate their interaction with the site pockets. A concise description of the method follows:(i) Construct each ligand molecule satisfying crystallographic bond lengths and bond angles,(ii) Construct some site pockets relative to the ligand molecules on the basis of an active conformation hypothesis. Some or all of the atoms of the active conformation may be assumed to occupy the site pockets to give its interaction. In other words, these atoms are representative of the site pockets (see ref 4 for a detailed explanation),(iii) Evaluate the geometrically allowed binding modes. By the term binding mode we mean which atom of the ligand goes to which site pocket. Due to the internal rotations around the various dihedral angles as well as the rigid rotations and translations of the ligand relative to the receptor, a large numberof geometrically feasible binding modes are possible, unless such motions are restricted by the steric requirements of the receptor site. 10 (iv) When an atom (or atoms) of the ligand enters a site pocket, it interacts with the site, and the interaction energy is a function of one or more physicochemical parameters of the atom. Assuming a linear function for the interaction, the binding energy of a particular binding mode may be given by