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.

Public Health Relevance

Integration of structural and dynamic aspects of drug resistance into drug design Project 3 - Sherman, Schrodinger Inc. We will be developing computational tools for the analysis and prediction of drug resistence mutations. These tools will enable analyzing various experimental and computational data generated in the project, with the goal of understanding drug resistance mechanisms and designing robust inhibitors that avoid resistance.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
1P01GM109767-01A1
Application #
8789532
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
Worcester
State
MA
Country
United States
Zip Code