501
Chapter 15
(How to) Profit from Molecular Dynamics-based
Ensemble Docking
Susanne von Grafenstein, Julian E. Fuchs and Klaus R. Liedl
© Springer Science+Business Media Dordrecht 2014
L. Gorb et al. (eds.), Application of Computational Techniques in Pharmacy and Medicine,
Challenges and Advances in Computational Chemistry and Physics 17,
DOI 10.1007/978-94-017-9257-8_15
K. R. Liedl () · S. von Grafenstein · J. E. Fuchs
Institute of General, Inorganic and Theoretical Chemistry,
University of Innsbruck, 6020 Innsbruck, Austria
e-mail: klaus.liedl@uibk.ac.at
Abstract Computational techniques have provided the field of drug discovery with
enormous advances over the last decades. The development of methods covering
dynamical aspects in protein–ligand binding is currently leading computer-aided
drug design to new levels of complexity as well as accuracy. In this book chapter we focus on molecular docking to structural ensembles generated by molecular
dynamics (MD) simulations. Does the incorporation of multiple receptor conformations allow pushing the borders for molecular docking or does it just lead to an
artificial increase in false positive hit rates due to a broader conformational space
of the receptor? We aim to identify guidelines for the best practice of molecular
dynamics simulation-based ensemble docking from recent studies in the literature.
Hence, we split the computational workflow for MD-based ensemble docking into
the respective steps starting from protein structure and compound database to in
silico hit lists. Thereby, we focus on the identification of successful strategies for
virtual screening.
15.1 Introduction
15.1.1 Structural Ensembles of Proteins
The view on proteins has evolved rapidly over past decades. Starting out from a static
view on protein structures, it has been recognized that proteins are intrinsically dynamic at room temperature. X-ray structures of proteins represent at best (assuming
no structural perturbation due to crystallization) one conformational state trapped in
Susanne von Grafenstein and Julian E. Fuchs contributed equally.
Chapter 15
(How to) Profit from Molecular Dynamics-based
Ensemble Docking
Susanne von Grafenstein, Julian E. Fuchs and Klaus R. Liedl
© Springer Science+Business Media Dordrecht 2014
L. Gorb et al. (eds.), Application of Computational Techniques in Pharmacy and Medicine,
Challenges and Advances in Computational Chemistry and Physics 17,
DOI 10.1007/978-94-017-9257-8_15
K. R. Liedl () · S. von Grafenstein · J. E. Fuchs
Institute of General, Inorganic and Theoretical Chemistry,
University of Innsbruck, 6020 Innsbruck, Austria
e-mail: klaus.liedl@uibk.ac.at
Abstract Computational techniques have provided the field of drug discovery with
enormous advances over the last decades. The development of methods covering
dynamical aspects in protein–ligand binding is currently leading computer-aided
drug design to new levels of complexity as well as accuracy. In this book chapter we focus on molecular docking to structural ensembles generated by molecular
dynamics (MD) simulations. Does the incorporation of multiple receptor conformations allow pushing the borders for molecular docking or does it just lead to an
artificial increase in false positive hit rates due to a broader conformational space
of the receptor? We aim to identify guidelines for the best practice of molecular
dynamics simulation-based ensemble docking from recent studies in the literature.
Hence, we split the computational workflow for MD-based ensemble docking into
the respective steps starting from protein structure and compound database to in
silico hit lists. Thereby, we focus on the identification of successful strategies for
virtual screening.
15.1 Introduction
15.1.1 Structural Ensembles of Proteins
The view on proteins has evolved rapidly over past decades. Starting out from a static
view on protein structures, it has been recognized that proteins are intrinsically dynamic at room temperature. X-ray structures of proteins represent at best (assuming
no structural perturbation due to crystallization) one conformational state trapped in
Susanne von Grafenstein and Julian E. Fuchs contributed equally.