The [3+2] Huisgen reaction was employed to access triazole containing staples that increased the helicity and target affinity of the parent peptide. Furthermore, the click-staples greatly increased cell penetration.
The rational design of ligands to bind to and perturb the activity of biological macromolecules stands as one of the longstanding goals of computational and medicinal chemistry. The overriding theme of this thesis is the development and application of computational tools that enable experimentalists to more efficiently tackle ligand design endeavors. In Chapter 1, we discuss the Fragment Optimized Growth (FOG) algorithm that is capable of generating virtual libraries of drug-like compounds. The Topology Classifier (TopClass) algorithm is also reported, which accurately classifies compounds as, for example, drugs or nondrugs. In Chapter 2, a Monte Carlo simulation method is described that is able to reproduce experimental trends in "stapled" peptide helical propensities. The incorporation of a hydrocarbon crosslink, or "staple," can dramatically increase the helix propensity of peptides. Through our computational study, we discovered that certain staples can stabilize quasi-stable decoy conformations, and that the removal of these states plays a major role in determining the helix stability of stapled peptides. In addition, we critically investigated why our method worked, exposing the underlying physical forces that stabilize stapled peptides. In Chapter 3, we use molecular modeling to help understand ring closing metathesis (RCM) yields and selectivity when tandem staples are employed to access "stitched" peptides, or when staples are placed in an i,i +3 manner. We also employ molecular modeling to understand the conformational stability of peptides that are constrained with such crosslinks. Finally, we use our method prospectively, and design staples that are conformationally constrained by cyclopropane moieties. In Chapter 4, we communicate the design and synthesis of click-stapled peptides.
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Collections of the Harvard University Archives. Dissertations.