Issue 13, 2014

Exploring structural requirements of leads for improving activity and selectivity against CDK5/p25 in Alzheimer's disease: an in silico approach

Abstract

A congeneric series of 224 cyclin-dependant kinase 5/p25 (CDK5/p25) inhibitors was exploited to understand the structural requirements for improving activity against CDK5/p25 and selectivity over CDK2. The CDK5/p25 enzyme complex plays a significant role in the formation of neurofibrillary tangles in Alzheimer's disease. In the present study, 2D-quantitative structure–activity relationship (2D-QSAR), group or fragment based QSAR (G-QSAR), and quantitative activity–activity relationship (QAAR) models were developed and validated with satisfactory performance as evidenced from statistical metrics, indicating the reliability and robustness of the models. The 2D-QSAR and G-QSAR models explore the structural requirements for improving activity, while the QAAR model facilitates the better understanding of features required for selectivity of the inhibitors. The docking study further provides information regarding the key active site residues and structural features important for proper binding in the active site of the CDK5/p25 complex.

Graphical abstract: Exploring structural requirements of leads for improving activity and selectivity against CDK5/p25 in Alzheimer's disease: an in silico approach

Supplementary files

Article information

Article type
Paper
Submitted
20 nov. 2013
Accepted
02 janv. 2014
First published
06 janv. 2014

RSC Adv., 2014,4, 6702-6709

Exploring structural requirements of leads for improving activity and selectivity against CDK5/p25 in Alzheimer's disease: an in silico approach

P. Ambure and K. Roy, RSC Adv., 2014, 4, 6702 DOI: 10.1039/C3RA46861E

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements