Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties

被引：51

作者：

Thansandote, Praew ^{[1
]}

Harris, Robert M. ^{[1
]}

Dexter, Hannah L. ^{[1
]}

Simpson, Graham L. ^{[1
]}

Pal, Sandeep ^{[1
]}

Upton, Richard J. ^{[1
]}

Valko, Klara ^{[1
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 02期

关键词：

Therapeutic peptides; Passive permeability; Physicochemical properties; Medicinal chemistry; Macrocyclic peptides; Protein-protein interactions; CYCLIC-PEPTIDES; MEMBRANE-PERMEABILITY; CYCLOSPORINE-A; N-METHYLATION; INTESTINAL PERMEABILITY; IN-VIVO; CONFORMATION; INHIBITORS; PREDICTION; DISCOVERY;

D O I：

10.1016/j.bmc.2014.11.034

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not only to improve passive permeability, but also to balance permeability with other physicochemical properties with the goal of understanding and applying the knowledge to develop active cyclic peptides into drug candidates. Evaluation of the methods herein suggest that increasing passive permeability often occurs at the expense of solubility and lipophilicity. Computational methods can be useful when attempting to predict and design features to balance these properties, though limitations were observed. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：322 / 327

页数：6

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