In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations

Xiaodong Gao; Liping Han; Yujie Ren

doi:10.3390/molecules21050591

In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations

Molecules. 2016 May 5;21(5):591. doi: 10.3390/molecules21050591.

Authors

Xiaodong Gao¹, Liping Han², Yujie Ren³

Affiliations

¹ School of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. [email protected].
² School of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. [email protected].
³ School of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. [email protected].

Abstract

Checkpoint kinase 1 (Chk1) is an important serine/threonine kinase with a self-protection function. The combination of Chk1 inhibitors and anti-cancer drugs can enhance the selectivity of tumor therapy. In this work, a set of 1,7-diazacarbazole analogs were identified as potent Chk1 inhibitors through a series of computer-aided drug design processes, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics simulations. The optimal QSAR models showed significant cross-validated correlation q² values (0.531, 0.726), fitted correlation r² coefficients (higher than 0.90), and standard error of prediction (less than 0.250). These results suggested that the developed models possess good predictive ability. Moreover, molecular docking and molecular dynamics simulations were applied to highlight the important interactions between the ligand and the Chk1 receptor protein. This study shows that hydrogen bonding and electrostatic forces are key interactions that confer bioactivity.

Keywords: Chk1 protein; CoMFA; CoMSIA; docking; molecular dynamics.

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Binding Sites
Carbazoles / chemistry*
Carbazoles / pharmacology
Checkpoint Kinase 1 / antagonists & inhibitors*
Computer Simulation
Drug Design
Hydrogen Bonding
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Quantitative Structure-Activity Relationship
Static Electricity

Substances

Antineoplastic Agents
Carbazoles
Protein Kinase Inhibitors
Checkpoint Kinase 1