Enhancing the hit-to-lead properties of lead optimization libraries

In this paper we address several issues in the design of lead optimization libraries. Multipharmacophore descriptors were first developed in the conte xt of designing diverse compound libraries. One reason for favoring such de scriptors is the importance of the pharmacophore hypothesis in understandin g the interaction of a compound with a protein target. Allied to this is th e proposal that sampling over all potential pharmacophores leads to diversi ty in a biologically relevant space. We present results in support of this argument and also demonstrate that such methods are applicable to the desig n of focused libraries where the aim is to design the library toward a know n lead or leads. This portability is important because it means that the sa me descriptors can be used for diverse library design, screening set select ion, and focused library design, giving a consistent approach. We also exam ine the question df designing libraries with improved pharmacokinetic prope rties and show that it is possible to derive simple and rapidly computable descriptors applicable to the prediction of drug transport properties. Furt hermore, these can be applied in the context of library design, although it may be necessary to synthesize libraries in a noncombinatorial manner to o btain the best results. To address this problem, we describe a Monte Carlo search procedure that allows the selection of a near-combinatorial subset i n which all library members satisfy the design criteria. We present an exam ple from our own work that illustrates how consideration of calculated log P, molecular weight, and polar surface area in the design of a combinatoria l library can lead to compounds with improved absorption characteristics as determined by experimental Caco-2 measurements.