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Unravelling novel congeners from acetyllysine mimicking ligand targeting a lysine acetyltransferase PCAF bromodomain.
- Source :
-
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2018 Dec; Vol. 36 (16), pp. 4303-4319. Date of Electronic Publication: 2018 Jan 04. - Publication Year :
- 2018
-
Abstract
- p300/CBP Associated Factor (PCAF) bromodomain (BRD), a lysine acetyltransferases, has emerged as a promising drug target as its dysfunction is linked to onset and progression of several diseases like cancer, diabetes, AIDS, etc. In this study, a three featured E-Pharmacophore (ARR) was generated based on acetyllysine mimicking inhibitor of PCAF BRD which is available as co-crystal structure (PDB ID: 5FDZ). It was used for filtering small molecule databases followed by molecular docking and consequently validated using enrichment calculation. The resulted hits were found to be congeners which show the predictive power of E-Pharmacophore hypothesis. Further, Induced Fit Docking method, Binding energy calculation, ADME prediction, Single Point Energy calculation and Molecular Dynamics simulation were performed to find better hits against PCAF BRD. Based on the results, it was concluded that Asn803, Tyr809 and Tyr802 along with a water molecule (HOH1001) plays crucial role in binding with inhibitor. It is also proposed that four hits from Life Chemicals database namely, F2276-0099, F2276-0008, F2276-0104 and F2276-0106 could act as potent drug molecules for PCAF BRD. Thus, the present study is strongly believed to have bright impact on rational drug design of potent and novel congeners of PCAF BRD inhibitors.
- Subjects :
- Algorithms
Binding Sites
Crystallography, X-Ray
Databases, Chemical
Enzyme Inhibitors metabolism
Enzyme Inhibitors pharmacology
Humans
Ligands
Lysine Acetyltransferases antagonists & inhibitors
Lysine Acetyltransferases metabolism
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Binding
Small Molecule Libraries metabolism
Small Molecule Libraries pharmacology
p300-CBP Transcription Factors antagonists & inhibitors
p300-CBP Transcription Factors metabolism
Enzyme Inhibitors chemistry
Lysine Acetyltransferases chemistry
Protein Domains
Small Molecule Libraries chemistry
p300-CBP Transcription Factors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1538-0254
- Volume :
- 36
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular structure & dynamics
- Publication Type :
- Academic Journal
- Accession number :
- 29228881
- Full Text :
- https://doi.org/10.1080/07391102.2017.1415820