Pickett SD, McLay IM, Clark DE
Rhone-Poulenc Rorer, Dagenham Research Centre, Essex, United Kingdom.
J Chem Inf Comput Sci. 2000 Mar;40(2):263-72. doi: 10.1021/ci990261w.
In this paper we address several issues in the design of lead optimization libraries. Multipharmacophore descriptors were first developed in the context of designing diverse compound libraries. One reason for favoring such descriptors is the importance of the pharmacophore hypothesis in understanding the interaction of a compound with a protein target. Allied to this is the proposal that sampling over all potential pharmacophores leads to diversity in a biologically relevant space. We present results in support of this argument and also demonstrate that such methods are applicable to the design of focused libraries where the aim is to design the library toward a known lead or leads. This portability is important because it means that the same descriptors can be used for diverse library design, screening set selection, and focused library design, giving a consistent approach. We also examine the question of designing libraries with improved pharmacokinetic properties and show that it is possible to derive simple and rapidly computable descriptors applicable to the prediction of drug transport properties. Furthermore, these can be applied in the context of library design, although it may be necessary to synthesize libraries in a noncombinatorial manner to obtain the best results. To address this problem, we describe a Monte Carlo search procedure that allows the selection of a near-combinatorial subset in which all library members satisfy the design criteria. We present an example from our own work that illustrates how consideration of calculated log P, molecular weight, and polar surface area in the design of a combinatorial library can lead to compounds with improved absorption characteristics as determined by experimental Caco-2 measurements.
在本文中，我们探讨了先导化合物优化库设计中的几个问题。多药效团描述符最初是在设计多样化化合物库的背景下开发的。青睐此类描述符的一个原因是药效团假说在理解化合物与蛋白质靶点相互作用方面的重要性。与此相关的是这样一种观点，即在所有潜在药效团上进行采样会导致在生物学相关空间中的多样性。我们给出了支持这一观点的结果，并证明此类方法适用于聚焦库的设计，其目的是针对一个或多个已知先导化合物来设计库。这种可移植性很重要，因为这意味着相同的描述符可用于多样化的库设计、筛选集选择和聚焦库设计，从而提供一种一致的方法。我们还研究了设计具有改善药代动力学性质的库的问题，并表明有可能推导出适用于预测药物转运性质的简单且快速可计算的描述符。此外，这些描述符可应用于库设计的背景中，尽管可能需要以非组合方式合成库以获得最佳结果。为了解决这个问题，我们描述了一种蒙特卡罗搜索程序，该程序允许选择一个近组合子集，其中所有库成员都满足设计标准。我们给出了我们自己工作中的一个例子，该例子说明了在组合库设计中考虑计算得到的log P、分子量和极性表面积如何能够导致具有如通过实验性Caco - 2测量所确定的改善吸收特性的化合物。
