title: Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity.
abstract: Suboptimal physical properties have been identified as a particular shortcoming of compounds in contemporary drug discovery, contributing to high attrition levels. An analysis of the relationship between hydrophobicity (calculated and measured) and approximately 100k measured kinetic solubility values has been undertaken. In line with the General Solubility Equation, estimates of hydrophobicity, particularly ACD clogD(pH7.4), give a useful indication of the likely solubility classification of particular molecules. Taking ACD clogD(pH7.4) values together with the number of aromatic rings in a given molecule provides enhanced prediction. The 'Solubility Forecast Index' (SFI=clogD(pH7.4)+#Ar) is proposed as a simple, yet effective, guide to predicting solubility. Moreover, analysis of measured distribution/partition coefficient values highlighted statistically significant shortcomings in the applicability of octanol/water as a model system for hydrophobicity determination with poorly soluble compounds.
authors.affiliation: Department of Analytical Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, UK. alan.p.hill@gsk.com
authors.forename: Alan P
authors.initials: AP
authors.lastname: Hill
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; D020003:1-Octanol