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.

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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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Kurt Yilmaz, Nese; Swanstrom, Ronald; Schiffer, Celia A (2016) Improving Viral Protease Inhibitors to Counter Drug Resistance. Trends Microbiol 24:547-57
Özer, Nevra; Özen, Ayşegül; Schiffer, Celia A et al. (2015) Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution. Evol Appl 8:185-98
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Ishima, Rieko (2015) Effects of radiation damping for biomolecular NMR experiments in solution: a hemisphere concept for water suppression. Concepts Magn Reson Part A Bridg Educ Res 44A:252-262
Cai, Yufeng; Myint, Wazo; Paulsen, Janet L et al. (2014) Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease. J Chem Theory Comput 10:3438-3448
Ragland, Debra A; Nalivaika, Ellen A; Nalam, Madhavi N L et al. (2014) Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease. J Am Chem Soc 136:11956-63
Kolli, Madhavi; Ozen, Ayşegül; Kurt-Yilmaz, Nese et al. (2014) HIV-1 protease-substrate coevolution in nelfinavir resistance. J Virol 88:7145-54
Özen, Ayşegül; Lin, Kuan-Hung; Kurt Yilmaz, Nese et al. (2014) Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease. Proc Natl Acad Sci U S A 111:15993-8