Accurate Prediction of Complex Structure and Affinity for a Flexible Protein Receptor and Its Inhibitor

In order to predict the accurate binding configuration as well as the binding affinity for a flexible protein receptor and its inhibitor drug, enhanced sampling with multicanonical molecular dynamics (McMD) simulation and thermodynamic integration (TI) were combined as a general drug docking method....

Full description

Saved in:
Bibliographic Details
Published in:Journal of chemical theory and computation 2017-06, Vol.13 (6), p.2389-2399
Main Authors: Bekker, Gert-Jan, Kamiya, Narutoshi, Araki, Mitsugu, Fukuda, Ikuo, Okuno, Yasushi, Nakamura, Haruki
Format: Article
Language:English
Subjects:
Affinity
Binding
Cell cycle
Computer simulation
Configurations
Cyclin-Dependent Kinase 2 - antagonists & inhibitors
Cyclin-Dependent Kinase 2 - chemistry
Cyclin-Dependent Kinase 2 - metabolism
Cyclin-dependent kinases
Docking
Free energy
Inhibitors
Malfunctions
Molecular chains
Molecular Docking Simulation
Molecular dynamics
Molecular Dynamics Simulation
Protein Conformation
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacology
Proteins
Thermodynamics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In order to predict the accurate binding configuration as well as the binding affinity for a flexible protein receptor and its inhibitor drug, enhanced sampling with multicanonical molecular dynamics (McMD) simulation and thermodynamic integration (TI) were combined as a general drug docking method. CDK2, cyclin-dependent kinase 2, is involved in the cell cycle regulation. Malfunctions in CDK2 can cause tumorigenesis, and thus it is a potential drug target. Here, we performed a long McMD simulation for docking the inhibitor CS3 to CDK2 starting from the unbound structure. Subsequently, a potential binding/unbinding pathway was given from the multicanonical ensemble, and the binding free energy was readily computed by TI along the pathway. Using this combination, the correct binding configuration of CS3 to CDK2 was obtained, and its affinity coincided well with the experimental value.
ISSN:1549-9618
1549-9626
DOI:10.1021/acs.jctc.6b01127