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Development of Potential Treatments for Congestive Heart Failure: a Multi-pronged Computational Approach

Hantz, Eric R
http://orcid.org/0000-0002-2588-7619
http://rave.ohiolink.edu/etdc/view?acc_num=osu1679996743566206

Abstract Details

, Doctor of Philosophy, Ohio State University, Biophysics.
This dissertation explored the creation of positive inotropes targeting the regulatory domain of cardiac troponin C (cNTnC). Upon calcium binding to cNTnC, a series of conformational changes occur in the muscle tissue ultimately leading to muscle contraction. The chapters in this dissertation discuss two approaches to increase cardiac muscle contractility and functionality in the diseased state. In the first approach, computational free energy method protocols were created for characterization of single point mutation effects on the calcium sensitivity of cNTnC. In the second, a structure-based drug design approach was taken to identify important features of previously identified calcium sensitizing small molecules and propose new directions for lead optimization. Chapter 2 introduced the free energy method adaptive steered molecular dynamics (ASMD). We developed a protocol for applying ASMD to determine the effects of previously deigned calcium sensitivity modulating mutations on cNTnC that have been well characterized in the literature. We observed the correct trends for all calcium sensitizing and desensitizing mutants, in conjunction with loop II alanine perturbations. Additionally, the potential of mean force accuracy was shown to increase substantially with increasingly slower speeds and using fewer trajectories. This study lays the foundation for ASMD as a valuable potential tool to support the design and characterization of novel mutations with potential therapeutic benefits. Chapter 3 explored the structure of cNTnC through an exhaustive single point mutagenesis study. Based on computational protein stability predictions focused on the loop regions of the EF-hand motifs, we identified and characterized eight mutations for their potential effects on calcium binding affinity in site II of cNTnC. We utilized two distinct methods to estimate calcium binding: adaptive steered molecular dynamics and thermodynamic integration (TI). We observed a sensitizing trend for all mutations based on the employed ASMD methodology. The TI results showed excellent agreement with experimentally known calcium binding affinity in wildtype cNTnC. Based on the TI results, five mutants were predicted to increase calcium sensitivity in site II. This chapter presents an interesting comparison of the two computational methods, which have both been shown to be valuable tools in characterizing the impacts of calcium sensitivity in mutant cNTnC systems. Chapter 4 introduced a generalizable protocol for improved results in structure-based drug design. We successfully applied the protocol to twenty target systems and identified the top three performing conformers for each of the targets. For a subset of five diverse cancer-related disease targets, we validated our approach through experimental testing of the top 50 compounds from a blind screening of a large, small molecule library. Our methods of receptor and compound selection resulted in the identification of 22 novel kinase inhibitors in the low μM-nM range. Additionally for a subset of five independent target systems, we demonstrated the utility of Gaussian accelerated Molecular Dynamics (GaMD) to thoroughly explore a target system’s potential energy surface and generate highly predictive receptor conformations. Chapter 5 applied the general principal structure-based drug design protocol developed in chapter 4 to the regulatory domain of cTnC. There is an increasing need for the development of small molecules that increase calcium sensitivity of cTn without altering systolic calcium concentration, thereby strengthening cardiac function. We took a rational computational approach for lead optimization based on lipophilic diphenyl moieties observed in several known sensitizers. Additionally, we explored the use of GaMD in sampling highly predictive receptor conformations based on NMR derived starting structures. This led to the identification of three novel low affinity binders, which had similar binding affinities to known positive inotrope trifluoperazine.
Steffen Lindert (Advisor)
Jonathan Davis (Committee Member)
Sherwin Singer (Committee Member)
Christopher Hadad (Committee Member)
Biophysics
computational chemistry; drug discovery; molecular dynamics

Recommended Citations

Citations

  • Hantz, E. R. (n.d.). Development of Potential Treatments for Congestive Heart Failure: a Multi-pronged Computational Approach [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1679996743566206

    APA Style (7th edition)

  • Hantz, Eric. Development of Potential Treatments for Congestive Heart Failure: a Multi-pronged Computational Approach. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1679996743566206.

    MLA Style (8th edition)

  • Hantz, Eric. "Development of Potential Treatments for Congestive Heart Failure: a Multi-pronged Computational Approach." Doctoral dissertation, Ohio State University. Accessed MAY 18, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1679996743566206

    Chicago Manual of Style (17th edition)

osu1679996743566206
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