Small molecule-based approach to chemistry and biology: Synthesis, measurement, and analysis

Small molecules have long played important roles in the advancement of biology; however, little meta-insight has been gained during this period. This thesis presents two studies that aim to uncover the relationships between chemical space and biological measurement space.;The first chapter comprises literature surveys of chemical descriptor space, biological measurement space (outputs), and analysis methods to link them. An emphasis on the role of diversity-oriented synthesis populating accessible chemical space (inputs) is offered.;The second chapter describes the methodology that uses well-defined inputs provided by diversity-oriented synthesis and robust readouts from a series of chemical genetic modifier screenings. Subsequent multidimensional data analysis confirms the intuition of the scientists yet adds methodical rigor, while simultaneously discovers novel patterns of biological activity that correlate with stereochemistry in a subtle and unexpected way. Significant variations in biological outcomes were found to result from the stereochemical and skeletal elements in small molecules. Such insights facilitate efficient searching and probing of chemical space.;The third chapter reports the development of analytical implements and illustrates that the relevance network is robust and flexible. The resulting analysis environment enables the visualization of significant associations between small molecules. A larger number of structurally and functionally heterogeneous inputs (small molecules) are efficiently examined based on a small-molecule annotation dataset and subsequently validated. Furthermore, novel hypotheses on the biological mechanisms of small molecules are proposed using already annotated small molecules.