In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction
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. 2014 Elsevier Inc. All rights reserved.
Keywords:
CDK9/cyclin T1 / Druggability mapping / Protein-protein interactions / Accelerated molecular dynamics / MM-GBSASource:
Journal of Molecular Graphics & Modelling, 2014, 50, 100-112Publisher:
- Elsevier Science Inc, New York
Funding / projects:
DOI: 10.1016/j.jmgm.2014.04.002
ISSN: 1093-3263
PubMed: 24769691
WoS: 000336875600011
Scopus: 2-s2.0-84899522347
Collections
Institution/Community
PharmacyTY - JOUR AU - Ranđelović, Jelena AU - Erić, Slavica AU - Savić, Vladimir PY - 2014 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2222 AB - 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. 2014 Elsevier Inc. All rights reserved. PB - Elsevier Science Inc, New York T2 - Journal of Molecular Graphics & Modelling T1 - In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction VL - 50 SP - 100 EP - 112 DO - 10.1016/j.jmgm.2014.04.002 ER -
@article{ author = "Ranđelović, Jelena and Erić, Slavica and Savić, Vladimir", year = "2014", 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. 2014 Elsevier Inc. All rights reserved.", publisher = "Elsevier Science Inc, New York", journal = "Journal of Molecular Graphics & Modelling", title = "In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction", volume = "50", pages = "100-112", doi = "10.1016/j.jmgm.2014.04.002" }
Ranđelović, J., Erić, S.,& Savić, V.. (2014). In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction. in Journal of Molecular Graphics & Modelling Elsevier Science Inc, New York., 50, 100-112. https://doi.org/10.1016/j.jmgm.2014.04.002
Ranđelović J, Erić S, Savić V. In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction. in Journal of Molecular Graphics & Modelling. 2014;50:100-112. doi:10.1016/j.jmgm.2014.04.002 .
Ranđelović, Jelena, Erić, Slavica, Savić, Vladimir, "In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction" in Journal of Molecular Graphics & Modelling, 50 (2014):100-112, https://doi.org/10.1016/j.jmgm.2014.04.002 . .