Publication: Expanding the conformational selection paradigm in protein-ligand docking
Program
School College Institute
GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
College of Engineering
College of Engineering
KU-Authors
KU Authors
Co-Authors
Nussinov, Ruth
Advisor
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Embargo Status
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Abstract
Conformational selection emerges as a theme in macromolecular interactions. Data validate it as a prevailing mechanism in protein-protein, protein-DNA, protein-RNA, and protein-small molecule drug recognition. This raises the question of whether this fundamental biomolecular binding mechanism can be used to improve drug docking and discovery. Actually, in practice this has already been taking place for some years in increasing numbers. Essentially, it argues for using not a single conformer, but an ensemble. The paradigm of conformational selection holds that because the ensemble is heterogeneous, within it there will be states whose conformation matches that of the ligand. Even if the population of this state is low, since it is favorable for binding the ligand, it will bind to it with a subsequent population shift toward this conformer. Here we suggest expanding it by first modeling all protein interactions in the cell by using Prism, an efficient motif-based protein-protein interaction modeling strategy, followed by ensemble generation. Such a strategy could be particularly useful for signaling proteins, which are major targets in drug discovery and bind multiple partners through a shared binding site, each with some-minor or major-conformational change.
Source:
Publisher:
Humana Press Inc
Subject
Biochemical research methods, Biochemistry, Molecular biology
Citation
Has Part
Source:
Computational Drug Discovery and Design
Book Series Title
Edition
DOI
10.1007/978-1-61779-465-0_5