Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis.
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Vassilios
V
Myrianthopoulos
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Nicolas
N
Gaboriaud-Kolar
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.
Cynthia
C
Tallant
Schrödinger Inc. , 222 Third Street, Cambridge, Massachusetts 02139, United States.
Michelle-Lynn
ML
Hall
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Stylianos
S
Grigoriou
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex , Brighton BN1 9RQ, U.K.
Peter Moore
PM
Brownlee
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.
Oleg
O
Fedorov
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.
Catherine
C
Rogers
Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
David
D
Heidenreich
Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Marek
M
Wanior
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Nikolaos
N
Drosos
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Nikitia
N
Mexia
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.
Pavel
P
Savitsky
Department of Clinical Therapeutics, School of Medicine, University of Athens , Mikras Asias 75, GR-11527 Athens, Greece.
Tina
T
Bagratuni
Department of Clinical Therapeutics, School of Medicine, University of Athens , Mikras Asias 75, GR-11527 Athens, Greece.
Efstathios
E
Kastritis
Department of Clinical Therapeutics, School of Medicine, University of Athens , Mikras Asias 75, GR-11527 Athens, Greece.
Evangelos
E
Terpos
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.
Panagis
P
Filippakopoulos
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.|Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Susanne
S
Müller
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Alexios-Leandros
AL
Skaltsounis
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex , Brighton BN1 9RQ, U.K.
Jessica Ann
JA
Downs
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Roosevelt Drive, Oxford OX3 7BN, U.K.|Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Stefan
S
Knapp
Department of Pharmacy, University of Athens , Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Emmanuel
E
Mikros
D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D004268:DNA-Binding Proteins; D008024:Ligands; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D054852:Small Molecule Libraries; D014157:Transcription Factors