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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Leidner, Florian; Kurt Yilmaz, Nese; Paulsen, Janet et al. (2018) Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease. J Chem Theory Comput 14:2784-2796
Nemmara, Venkatesh V; Subramanian, Venkataraman; Muth, Aaron et al. (2018) The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs). ACS Chem Biol 13:712-722
Ilina, Tatiana V; Slack, Ryan L; Elder, John H et al. (2018) Effect of tRNA on the Maturation of HIV-1 Reverse Transcriptase. J Mol Biol 430:1891-1900
Khan, Shahid N; Persons, John D; Paulsen, Janet L et al. (2018) Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance. Biochemistry 57:1652-1662
Persons, John D; Khan, Shahid N; Ishima, Rieko (2018) An NMR strategy to detect conformational differences in a protein complexed with highly analogous inhibitors in solution. Methods 148:9-18
Potempa, Marc; Lee, Sook-Kyung; Kurt Yilmaz, Nese et al. (2018) HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites. J Mol Biol 430:5182-5195
Tilvawala, Ronak; Nguyen, Son Hong; Maurais, Aaron J et al. (2018) The Rheumatoid Arthritis-Associated Citrullinome. Cell Chem Biol 25:691-704.e6
Venev, Sergey V; Zeldovich, Konstantin B (2018) Thermophilic Adaptation in Prokaryotes Is Constrained by Metabolic Costs of Proteostasis. Mol Biol Evol 35:211-224
Wong, Alicia; Bryzek, Danuta; Dobosz, Ewelina et al. (2018) A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA. J Immunol 200:2327-2340
Sun, Bo; Dwivedi, Nishant; Bechtel, Tyler J et al. (2017) Citrullination of NF-?B p65 promotes its nuclear localization and TLR-induced expression of IL-1? and TNF?. Sci Immunol 2:

Showing the most recent 10 out of 22 publications