Among currently marketed pharmaceutical compounds, there are examples with effective clinical response, despite predictions of unfavorable oral bioavailability by high-throughput computational screening methods. To account for this fact, it has been proposed that these drugs may possess sufficient molecular flexibility, so that hydrophilic groups can be exposed to polar environments and hidden from apolar environments. This proposal describes the development of computational methods for discovering hydrophilic and lipophilic conformations in pharmaceutical compounds and identifying the environment-dependent transition paths between them. We have designed the research so that the computational studies work in a feedback loop, with specific experimental work carried out at Pharmacia Corporation. The resulting convergence of theoretical and experimental studies will enable more complete understanding of the biophysical mechanisms that influence the connection between molecular flexibility and drug bioavailability. The involvement of undergraduate students in this project will enhance our institution's existing strength in engaging and mentoring students in biomedical research.
