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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 represent a useful training set for computational solubility prediction.

SUBMITTER: Guha R

PROVIDER: S-EPMC3236531 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Exploratory analysis of kinetic solubility measurements of a small molecule library.

Guha Rajarshi R Dexheimer Thomas S TS Kestranek Aimee N AN Jadhav Ajit A Chervenak Andrew M AM Ford Michael G MG Simeonov Anton A Roth Gregory P GP Thomas Craig J CJ

Bioorganic & medicinal chemistry 20110513 13

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 ...[more]

PMID: 21640593

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Project description:Applications of synthetic biology spanning human health, industrial bioproduction, and ecosystem monitoring often require small molecule sensing capabilities, typically in the form of genetically encoded small molecule biosensors. Critical to the deployment of greater numbers of these systems are methods that support the rapid development of such biosensors against a broad range of small molecule targets. Here, we use a previously developed method for selection of RNA biosensors against unmodified small molecules (DRIVER) to perform a selection against a densely multiplexed mixture of small molecules, representative of those employed in high-throughput drug screening. Using a mixture of 5,120 target compounds randomly sampled from a large diversity drug screening library, we performed a 95-round selection and then analyzed the enriched RNA biosensor library using next generation sequencing (NGS). From our analysis, we identified RNA biosensors with at least 2-fold change in signal in the presence of at least 217 distinct target compounds with sensitivities down to 25 nM. Although many of these biosensors respond to multiple targets, clustering analysis indicated at least 150 different small-molecule sensing patterns. We also built a classifier that was able to predict whether the biosensors would respond to a new compound with an average precision of 0.82. Since the target compound library was designed to be representative of larger diversity compound libraries, we expect that the described approach can be used with similar compound libraries to identify aptamers against other small molecules with a similar success rate. The new RNA biosensors (or their component aptamers) described in this work can be further optimized and used in applications such as biosensing, gene control, or enzyme evolution. In addition, the data presented here provide an expanded compendium of new RNA aptamers compared to the 82 small molecule RNA aptamers published in the literature, allowing further bioinformatic analyses of the general classes of small molecules for which RNA aptamers can be found.

Dataset Information

Exploratory analysis of kinetic solubility measurements of a small molecule library.

Publications

Exploratory analysis of kinetic solubility measurements of a small molecule library.

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