Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1

来自 Elsevier

喜欢 0

阅读量：

372

作者：

CA Lipinski，F Lombardo，BW Dominy，PJ Feeney

展开

摘要：

Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting ‘the rule of 5’ predicts that poor absorption or permeation is more likely when there are more than 5 Hbond donors, 10 Hbond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.

展开

关键词：

Rule of 5 Computational alert Poor absorption or permeation MWT MLogP HBond donors and acceptors Turbidimetric solubility Thermodynamic solubility Solubility calculation