Design, synthesis, and evaluation of conformationally-constrained Grb2 SH2 ligands and a concise total synthesis of lycopladine A
MetadataShow full item record
Conformationally constrained ligands and their flexible analogues were prepared as inhibitors of the Grb2 SH2 domain in order to study the structural and energetic effects of ligand preorganization in protein-ligand interactions. The compounds were prepared by using trans-cyclopropane-containing amino acid mimics, macrocyclization, or [alpha,alpha]-disubstituted amino acid residues. All trans-cyclopropane containing peptides were more potent than their corresponding succinate containing analogues due to an enthalpic advantage. Surprisingly, the binding of constrained peptides to the domain was entropically disfavored relative to their flexible controls. Effects of proton transfer and desolvation as being the source of the unprecedented entropic penalty for the constrained ligands relative to their respective controls were precluded, and X-ray crystallographic studies revealed that the binding conformations for the respective cyclopropane and succinate containing ligands were similar. This led us to believe that differential changes in protein dynamics may occur upon binding of the constrained and flexible ligands, which could contribute to the observed binding energetics. Two 23-membered macrocyclic ligands were slightly more potent than their corresponding linear controls. The amino acids used to link the N- and C-termini of the linear peptides to form the macrocycles were found to affect the energetics of binding. In one case, the 23-membered macrocycle was more potent than its control due to an entropic advantage, whereas the other 23-membered macrocycle was more potent than its control because it benefited from an enthalpic advantage. [alpha,alpha]-Disubstituted and [alpha]-monosubstituted residues that varied in hydrophobic character were incorporated into Grb2 SH2 domain binding tripeptides, and binding became more favorable as nonpolar surface area increased only for the set of tripeptides possessing cyclic [alpha,alpha]-disubstituted residues. The increase in affinity was due to an increasing enthalplic term, whereas the entropy of binding became less favorable. A total synthesis of (±)-lycopladine A was achieved in five steps from known compounds. The tricyclic core of the natural product was prepared utilizing a novel two-step sequence comprising a conjugate addition of a metalated picoline derivative followed by an intramolecular enolate arylation. It was demonstrated that the natural product existed in a solvent dependent equilibrium with its isomeric lactol.
Showing items related by title, author, creator and subject.
Synthesis and Structural Analyses of Phenylethynyl-Substituted Tris(2-Pyridylmethyl)Amines and their Copper(II) Complexes Lim, Jaebum; Lynch, Vincent M.; Edupuganti, Ramakrishna; Ellington, Andrew; Anslyn, Eric V. (2016-05)Three new tris(2-pyridylmethyl) amine-based ligands possessing phenylethynyl units have been prepared using Sonogashira couplings and substitution reactions. Copper(II) complexes of those tetradentate ligands have also ...
Design, synthesis, and thermodynamic evaluation of peptidomimetic ligands binding to the Src SH2 domain Farley, Christopher Alexander (2018-05-03)The ability to predict protein-ligand binding affinities is a difficult and elusive goal in the field of molecular recognition. Models exist to predict binding energetics; however, they are not always capable of considering ...
Conducting metallopolymers with tridentate ligands and coordination chemistry with corresponding model compounds Keskin, Şeyma; 0000-0001-8677-0265 (2018-06-20)Conducting polymers that contain metals are remarkable materials, because they have the properties of both organic backbones and metals. Depending on the position of the metal relative to the conjugated backbone, i.e. ...