Fernandez, Ariel2011-07-252011-07-252009Zhang, Xi. "Specificity in the druggable kinome: Molecular basis and its applications." (2009) Diss., Rice University. <a href="https://hdl.handle.net/1911/61945">https://hdl.handle.net/1911/61945</a>.https://hdl.handle.net/1911/61945Rational design of kinase inhibitors remains a challenge partly because there is no clear delineation of the molecular features that direct the pharmacological impact towards clinically relevant targets. In this thesis, we focus on a structural marker and construct a kinase classifier that enables the accurate prediction of pharmacological differences. Our indicator is a microenvironmental descriptor that quantifies the propensity for water exclusion around preformed polar pairs. The results suggest that targeting polar dehydration patterns heralds a new generation of drugs that enable a tighter control of specificity than designs aimed at promoting ligand-kinase pairwise interactions. As an application of the structural marker, we introduce a computational screening approach which provides a tool for extensive screening that uses experimentally obtained small-scale profiles as input data and makes predictions for a larger kinase set. These predictions result from a propagation of the reduced profile, exploiting a structural comparison of kinases based on a feature-similarity matrix. The comparison focuses on a molecular marker for specificity and promiscuity of kinase inhibitors. Our approach enables the computational high-throughput screening of entire libraries of compounds to search for suitable leads, mapping their inhibitory impact on a sizable sample of the human kinome. Yet another application of the structural marker is advocated by illustrating its cleaning efficacy. In this regard, we reassess the possibility to turn multi-target drugs into real clinical opportunities through judicious redesign. A general cleaning strategy, which adopts the structural marker as redesigning instruction, is proposed and exemplified by a workable approach.application/pdfengCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Biomedical engineeringBiophysicsThesis