In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction

Jelena Randjelovic; Slavica Eric; Vladimir Savic

doi:10.1016/j.jmgm.2014.04.002

In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction

J Mol Graph Model. 2014 May:50:100-12. doi: 10.1016/j.jmgm.2014.04.002. Epub 2014 Apr 13.

Authors

Jelena Randjelovic¹, Slavica Eric², Vladimir Savic³

Affiliations

¹ University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia; University of Belgrade, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address: jelenar@pharmacy.bg.ac.rs.
² University of Belgrade, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia.
³ University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address: vladimir.savic@pharmacy.bg.ac.rs.

PMID: 24769691
DOI: 10.1016/j.jmgm.2014.04.002

Abstract

In order to design a small molecule which potentially may interfere with CDK9/cyclin T1 complex formation and therefore influence its physiological role, a computational study of dynamics and druggability of CDK9 binding surface was conducted. Druggability estimates and pocket opening analyses indicated binding regions of cyclin T1 residues, Phe 146 and Lys 6, as starting points for the design of small molecules with the potential to inhibit the CDK9/cyclin T1 association. A pharmacophore model was created, based on these two residues and used to select potential inhibitor structures. Binding energies of the inhibitors were estimated with MM-GBSA. A good correlation of MM-GBSA energies and FTMap druggability predictions was observed. Amongst studied compounds a derivative of 2-amino-8-hydroxyquinoline was identified as the best potential candidate to inhibit CDK9/cyclin T1 interactions.

Keywords: Accelerated molecular dynamics; CDK9/cyclin T1; Druggability mapping; MM-GBSA; Protein–protein interactions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cyclin T / metabolism*
Cyclin-Dependent Kinase 9 / metabolism*
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Protein Binding / drug effects
Quinolines / chemistry

Substances

Cyclin T
Enzyme Inhibitors
Quinolines
quinoline
Cyclin-Dependent Kinase 9