Exploratory analysis of kinetic solubility measurements of a small molecule library

Abstract

Kinetic solubility measurements using prototypical assay buffer conditions are presented for a ~58,000 member library of small molecules. Analyses of the data based upon physical and calculated properties of each individual molecule were performed and resulting trends were considered in the context of commonly held opinions of how physicochemical properties influence aqueous solubility. We further analyze the data using a decision tree model for solubility prediction and via a multi-dimensional assessment of physicochemical relationships to solubility in the context of specific ‘rule-breakers’ relative to common dogma. The role of solubility as a determinant of assay outcome is also considered based upon each compound’s cross-assay activity score for a collection of publicly available screening results. Further, the role of solubility as a governing factor for colloidal aggregation formation within a specified assay setting is examined and considered as a possible cause of a high cross-assay activity score. The results of this solubility profile should aid chemists during library design and optimization efforts and represents a useful training set for computational solubility prediction.

Exploring structure–activity data using the landscape paradigm

“…It is important to remember that an activity cliff, in general, arises due to a key interaction between a specific feature of a small molecule and the receptor. Thus the activity cliff concept and associated analyses cannot be applied to bulk properties such as solubility (although a number of activity cliff‐like cases can be found in large collections of solubility data49). In many cases, these key ligand–receptor interactions can be elucidated via other means, and thus could be used to identify activity cliffs prospectively.…”

Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

“…Using the criteria outlined by Guha et al . 42 , test agents were characterized as exhibiting low aqueous solubility (< 10 μg/mL), medium solubility (10 μg/mL – 60 μg/mL), or high solubility (>60 μg/mL). The solubility result for 4b is presented in Supplementary Table 3.…”

Selection of effective cocrystals former for dissolution rate improvement of active pharmaceutical ingredients based on lipoaffinity index

“…Many examples of such cases can be found in the literature, including cocrystals but also other types of solid mixtures such as inclusion complexes with cyclodextrins (Dua et al, 2011;M Badr-Eldin et al, 2013;Thiry et al, 2017aThiry et al, , 2017b and dispersions with soluble polymers (Brough et al, 2015;Choi and Park, 2017;Ibrahim et al, 2010;Maggi et al, 2013;Six et al, 2004;Thiry et al, 2017a). Noteworthy, Guha et al, (2011), found that APIs can be classified in terms of their kinetic solubility values using different hydrophilicity indices. Hence, all three molecular descriptors identified during screening procedure are related to differences in the polarity of cocrystals components.…”