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How proteins bind macrocycles.

Abstract：

:The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Villar EA,Beglov D,Chennamadhavuni S,Porco JA Jr,Kozakov D,Vajda S,Whitty A

doi

10.1038/nchembio.1584

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

723-31

issue

9

eissn

1552-4450

issn

1552-4469

pii

nchembio.1584

journal_volume

10

pub_type

杂志文章

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