Cyclic Peptide Design Guided by Residual Dipolar Couplings, J-Couplings, and Intramolecular Hydrogen Bond Analysis.

Autor:	Farley KA; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Che Y; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Navarro-Vázquez A; Departamento de Química Fundamental, CCEN , Universidade Federal de Pernambuco , Cidade Universitária, Recife , PE 50740-560 , Brazil., Limberakis C; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Anderson D; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Yan J; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Shapiro M; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Shanmugasundaram V; Medicinal Sciences, Pfizer Worldwide R&D , Eastern Point Road , Groton , Connecticut 06340 , United States., Gil RR; Department of Chemistry , Carnegie Mellon University , Pittsburgh , Pennsylvania 15213 , United States.
Jazyk:	angličtina
Zdroj:	The Journal of organic chemistry [J Org Chem] 2019 Apr 19; Vol. 84 (8), pp. 4803-4813. Date of Electronic Publication: 2019 Jan 15.
DOI:	10.1021/acs.joc.8b02811
Abstrakt:	Cyclic peptides have long tantalized drug designers with their potential ability to combine the best attributes of antibodies and small molecules. An ideal cyclic peptide drug candidate would be able to recognize a protein surface like an antibody while achieving the oral bioavailability of a small molecule. It has been hypothesized that such cyclic peptides balance permeability and solubility using their solvent-dependent conformational flexibility. Herein we report a conformational deconvolution NMR methodology that combines residual dipolar couplings, J-couplings, and intramolecular hydrogen bond analysis along with conformational analysis using molecular dynamics simulations and density functional theory calculations for studying cyclic peptide conformations in both low-dielectric solvent (chloroform) and high-dielectric solvent (DMSO) to experimentally study the solvent-dependent conformational change hypothesis. Taken together, the combined experimental and computational approaches can illuminate conformational ensembles of cyclic peptides in solution and help identify design opportunities for better permeability.
Databáze:	MEDLINE
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