ABSTRACT
The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSARs). Herein, we develop QSAR models that quantitatively predict both thermodynamic- and kinetic-based binding parameters of small molecules and the HIV-1 transactivation response (TAR) RNA model system. Small molecules bearing diverse scaffolds were screened against TAR using surface plasmon resonance. Multiple linear regression (MLR) combined with feature selection afforded robust models that allowed direct interpretation of the properties critical for both binding strength and kinetic rate constants. These models were validated with new molecules, and their accurate performance was confirmed via comparison to ensemble tree methods, supporting the general applicability of this platform.
Subject(s)
Quantitative Structure-Activity Relationship , RNA , Drug Discovery , Humans , Models, BiologicalABSTRACT
Often, government agencies and survey organizations know the population counts or percentages for some of the variables in a survey. These may be available from auxiliary sources, for example, administrative databases or other high quality surveys. We present and illustrate a model-based framework for leveraging such auxiliary marginal information when handling unit and item nonresponse. We show how one can use the margins to specify different missingness mechanisms for each type of nonresponse. We use the framework to impute missing values in voter turnout in a subset of data from the U.S. Current Population Survey (CPS). In doing so, we examine the sensitivity of results to different assumptions about the unit and item nonresponse.
