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The Recognition of Unrelated Ligands by Identical Proteins.

Abstract：

:Unrelated ligands, often found in drug discovery campaigns, can bind to the same receptor, even with the same protein residues. To investigate how this might occur, and whether it might be typically possible to find unrelated ligands for the same drug target, we sought examples of topologically unrelated ligands that bound to the same protein in the same site. Seventy-six pairs of ligands, each bound to the same protein (152 complexes total), were considered, classified into three groups. In the first (31 pairs of complexes), unrelated ligands interacted largely with the same pocket residues through different functional groups. In the second group (39 pairs), the unrelated ligand in each pair engaged different residues, though still within the same pocket. The smallest group (6 pairs) contained ligands with different scaffolds but with shared functional groups interacting with the same residues. We found that there are multiple chemically unrelated but physically similar functional groups that can complement any given local protein pocket; when these functional group substitutions are combined within a single molecule, they lead to topologically unrelated ligands that can each well-complement a site. It may be that many active and orthosteric sites can recognize topologically unrelated ligands.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Pottel J,Levit A,Korczynska M,Fischer M,Shoichet BK

doi

10.1021/acschembio.8b00443

subject

Has Abstract

pub_date

2018-09-21 00:00:00

pages

2522-2533

issue

9

eissn

1554-8929

issn

1554-8937

journal_volume

13

pub_type

杂志文章

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