Integration of structural and dynamic aspects of drug resistance into drug design

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Project Summary Integration of structural and dynamic aspects of drug resistance into drug design Project 3 - Sherman, Schrodinger Inc. We will be developing structure-based tools to aid in the analysis and prediction of drug resistance mutations. We will integrate the substrate envelope hypothesis into a docking algorithm to account for resistance mutations during virtual screening. We will also use free energy methods to assess the impact of putative resistance mutations. The list of potential resistance mutations will come from deep sequencing performed by Project 2. First, we will develop a suite of tools for utilizing deep sequence information to generate possible resistant mutants. In addition, we will study resistance mutations distal from the binding site using molecular dynamics and mutual information theory. Finally, we will explore the importance of explicit water molecules on drug resistance using a combination of molecular dynamics and inhomogeneous solvation theory. This combined approach, which includes experimental, empirical, and physics-based approaches, should add significant value to the design of inhibitors with better resistance profiles.