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Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.

Abstract：

:Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock α-GID and its analogs to an α4β2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive α-GID mutants (α-GID[A10V], α-GID[V13I], and α-GID[V13Y]) and one inactive variant (α-GID[A10Q]). Two mutants, α-GID[A10V] and α-GID[V13Y], had substantially reduced potency at the human α7 nAChR relative to α-GID, a desirable feature for α-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the α-GID:α4β2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Leffler AE,Kuryatov A,Zebroski HA,Powell SR,Filipenko P,Hussein AK,Gorson J,Heizmann A,Lyskov S,Tsien RW,Poget SF,Nicke A,Lindstrom J,Rudy B,Bonneau R,Holford M

doi

10.1073/pnas.1703952114

subject

Has Abstract

pub_date

2017-09-19 00:00:00

pages

E8100-E8109

issue

eissn

0027-8424

issn

1091-6490

pii

1703952114

journal_volume

114

pub_type

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Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.