A Griewel

Angela M Henzler

Benjamin Schulz

J Schlosser

Matthias Rarey

MJ Hartshorn

Sascha Urbaczek

T Lippert

Journal of Cheminformatics

English

PubMed

Crossref

A flexible-hydrogen interaction model for protein-ligand docking

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POSTER PRESENTATION Open Access
A flexible-hydrogen interaction model for
protein-ligand docking
Angela M Henzler*, Sascha Urbaczek, Benjamin Schulz, Matthias Rarey
From 7th German Conference on Chemoinformatics: 25 CIC-Workshop
Goslar, Germany. 6-8 November 2011
Although some docking methods accounting for protein
flexibility exist, most large scale virtual screening
approaches work with rigid protein models. A first step
towards flexibility integration is the consideration of
degrees of freedom resulting from hydrogens, especially,
if involved in hydrogen bonding. To account for this
type of flexibility, we present a flexible-hydrogen inter-
action model as part of a descriptor-based docking
technique.
The model discretizes interaction spheres of rigid and
flexible hydrogen-bond donors and acceptors as interac-
tion spots. A spot has an associated interaction direction
which indicates hydrogen or lone pair orientation, and
thus, the potential location of a hydrogen-bond counter-
part. This new flexible-hydrogen interaction model is
combined with a novel approach to describe hydropho-
bic contacts. Both are introduced in our descriptor-
based docking approach named TrixX [1]. TrixX han-
dles ligand flexibility by applying a conformer ensemble
approach [2]. The latter allows for the use of efficient
indexing techniques upon virtual screening. The discre-
tized, flexible-hydrogen model proposes potential hydro-
gen and lone pair positions. However, these proposals
may still slightly differ from their actual location which
can be only determined in presence of pose and active
site, i. e., after the docking stage. In order to grant a
thorough assessment of hydrogen bonds, thereby, the
predicted poses are forwarded to an efficient post-opti-
mization of the hydrogen-bond network. It optimally
aligns hydrogens, identifies favorable tautomeric and
protonation states, and evaluates the predicted pose [3].
Redocking of the Astex Diverse Set [4] shows that the
described docking method produces results in good
agreement with co-crystalized ligand structures. Several
case studies using different levels of discretization and
post-optimization, illustrate the influence of our pre-
sented procedures in ligand placement and scoring. The
studies highlight the impact of flexible hydrogens and
lone pairs during docking and confirm the introduction
of our flexible hydrogen model.
Published: 1 May 2012
References
1. Schlosser J, Rarey M: Beyond the Virtual Screening Paradigm: Structure-
Based Searching for New Lead Compounds. J Chem Inf Model 2009,
49:800-809.
2. Griewel A, Kayser O, Schlosser J, Rarey M: Conformational Sampling for
Large-Scale Virtual Screening: Accuracy versus Ensemble Size. J Chem Inf
Model 2009, 49:2303-2311.
3. Lippert T, Rarey M: Fast automated placement of polar hydrogen atoms
in protein-ligand complexes. J Cheminform 2009, 1:13.
4. Hartshorn MJ, et al: Diverse, High-Quality Test Set for the Validation of
Protein-Ligand Docking Performance. J Med Chem 2007, 50:726-741.
doi:10.1186/1758-2946-4-S1-P14
Cite this article as: Henzler et al.: A flexible-hydrogen interaction model
for protein-ligand docking. Journal of Cheminformatics 2012 4(Suppl 1):
P14.
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Center for Bioinformatics, University of Hamburg, Hamburg, 20146, Germany
Henzler et al. Journal of Cheminformatics 2012, 4(Suppl 1):P14
http://www.jcheminf.com/content/4/S1/P14
© 2012 Henzler et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.


Beyond the Virtual Screening Paradigm: StructureBased Searching for New Lead Compounds.

Conformational Sampling for Large-Scale Virtual Screening: Accuracy versus Ensemble Size. J Chem Inf Model

Fast automated placement of polar hydrogen atoms in protein-ligand complexes.

High-Quality Test Set for the Validation of Protein-Ligand Docking Performance. J Med Chem

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3341315

A flexible-hydrogen interaction model for protein-ligand docking

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