Protein-ligand docking accounting for receptor side chain and global flexibility in normal modes: Evaluation on kinase inhibitor cross docking

Andreas May, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Efficient treatment of conformational changes during docking of drug-like ligands to receptor molecules is a major computational challenge. A new docking methodology has been developed that includes ligand flexibility and both global backbone flexibility and side chain flexibility of the protein receptor. Whereas side chain flexibility is based on a discrete rotamer approach, global backbone conformational changes are modeled by relaxation in a few precalculated soft collective degrees of freedom of the receptor. The method was applied to docking of several known cyclin dependent kinase 2 inhibitors to the unbound kinase structure and to cross-docking of inhibitors to several bound kinase structures. Significant improvement of ranking and deviation of predicted binding geometries from experiment was obtained compared to docking to a rigid receptor. The inclusion of only the soft collective degrees of freedom during docking resulted in improved docking performance at a very modest increase (doubling) of the computational demand.

Original languageEnglish
Pages (from-to)3499-3506
Number of pages8
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
StatePublished - 26 Jun 2008
Externally publishedYes

Fingerprint

Dive into the research topics of 'Protein-ligand docking accounting for receptor side chain and global flexibility in normal modes: Evaluation on kinase inhibitor cross docking'. Together they form a unique fingerprint.

Cite this