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1 Supporting Information Discovery and optimization of a selective ligand for the Switch/Sucrose Non-Fermenting-related bromodomains of Polybromo protein-1 by the use of virtual screening and hydration analysis. Vassilios Myrianthopoulos 1, Nicolas Gaboriaud-Kolar 1, Cynthia Tallant 2-3, Michelle-Lynn Hall 4, Stylianos Grigoriou 1, Peter Moore Brownlee 5, Oleg Fedorov 2-3, Catherine Rogers 2-3, David Heidenreich 6, Marek Wanior 6, Nikolaos Drosos 1, Nikitia Mexia 1, Pavel Savitsky 2-3, Tina Bagratuni 7, Efstathios Kastritis 7, Evangelos Terpos 7, Panagis Filippakopoulos 2-3, Susanne Müller 2,3,6, Alexios-Leandros Skaltsounis 1, Jessica Ann Downs 5, Stefan Knapp 2,3,6* and Emmanuel Mikros 1 * 1 Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771, Athens, Greece. 2 Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. 3 Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Roosevelt Drive, Oxford OX3 7BN, UK. 4 Schrödinger Inc., 222 Third Street, Cambridge MA 02139, United States. 5 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton BN1 9RQ, UK. 6 Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Max-von-Laue-Str. 9, D Frankfurt am Main, Germany. 7 Department of Clinical Therapeutics, School of Medicine, University of Athens, Mikras Asias 75, GR-11527, Athens, Greece.
2 Contents: Table S1. Canvas FP combinations used for VS. Table S2. Structures and T m values of 40 compounds screened by DSF. Table S3. Screening T m curves of compounds with significant binding affinity for studied BRDs. Table S4. X-ray crystallography data collection and refinement statistics. Table S5. DSF data for the studied compounds. Table S6. ITC data for the studied compounds. Figure S1. The network of hydrogen bonds anchoring the buried water molecule in the 9-PB1(5) complex. Figure S2. 1BR-TERT cells viability assay of 12. S2
3 Fingerprint type Atom typing method Scaling MOLPRINT2D Carhart no scaling MOLPRINT2D Daylight no scaling Radial Carhart square root feature Radial Carhart square root unity Radial Daylight no scaling Radial Daylight square root feature Radial ElemR no scaling Radial Hybrid square root feature Radial Hybrid square root feature Radial Mol2 no scaling Radial Mol2 square root feature Table S1. The 11 most efficient FP combinations of Canvas used subsequently for screening. These FP screens afforded high enrichment quantified as the enrichment factor at 20% of screened library (EF 20% ). The 11 FP combinations affording high recovery of known actives showed an EF 20% greater than 2.25 while the remaining combinations resulted to lower EF 20% ranging from 0 to The EF 20% ranges from 0 (no enrichment) to 5 (maximum enrichment). S3
4 Compound Structure PB1(5) T m ( C) BRD4(2) NSC NSC NSC NSC45837 (3) NSC48742 (4) NSC S4
5 NSC55495 (5) NSC55917 (6) NSC NSC76484 (8) NSC NSC97717 (7) S5
6 NSC NSC NSC NSC NSC NSC S6
7 NSC NSC NSC NSC NSC S7
8 NSC NSC NSC NSC NSC S8
9 NSC NSC NSC NSC NSC (9) NSC S9
10 NSC NSC NSC NSC NSC NSC S10
11 Table S2. The 40 compounds from NCI/DTP that were evaluated in the DSF screen and their T m values towards PB1(5) and BRD4(2). The compounds were screened at 200µM while the protein was at 20µM. Shown are the compounds, their NSC code numbers and the respective T m values. Stabilization values exceeding 1.5 C are marked in bold. Compound 9 showed significant affinity for PB1(5) and was thus subjected to co-crystallization and X-ray crystallography to determine its binding mode to PB1(5) and suggest possible routes for optimization. S11
12 Compound T m PB1(5) T m BRD4(2) 0 C 0.8 C 3 (NSC45837) C, R -0.2 C 2.0 C 4 (NSC48742) C, R 0 C 1.6 C 5 (NSC55495) G 0.6 C 1.8 C 6 (NSC55917) G S12
13 -0.4 C 1.5 C 7 (NSC97717) G 0.1 C 3.2 C 8 (NSC76484) C, R 4.1 C 1.9 C 9 (NSC356476) G Table S3. The T m curves of the seven compounds showing measurable binding affinity in the DSF screen. The compounds were screened at 200µM while the protein was at 20µM. Shown are the NSC number of the compounds and the T m in C observed for PB1(5) and BRD4(2). In the panel BRD2(2), BRD3(2), BRD4(1) and BRDT were included in addition to BRD4(2) and PB1(5) but no binding was observed for those proteins. The screening methodology affording each compound is shown below the NSC code; C: Canvas; G: Glide; R: ROCS. S13
14 PDB ID 5II1 5HRV 5HRW Protein PB1(5) PB1(5) PB1(5) Compound Space group P C P Cell dimensions: a, b, c (Å) α, β, γ (deg) Resolution* (Å) (2.02) (1.70) (1.80) Unique observations* (2488) (883) (1312) Completeness* (%) 99.8 (100.0) 99.3 (89.7) 97.4 (93.2) Redundancy* 4.3 (4.3) 7.8 (4.2) 5.0 (4.8) Rmerge* (0.671) (0.360) (0.735) I/σI* 12.5 (2.0) 28.2 (3.9) 18.5 (2.2) Refinement Resolution (Å) R work / R free (%) 18.8/ / / Number of atoms (protein/other/water) 1826/30/ / 20 / / 59 / 81 B-factors (A 2 ) (protein/other/water) 36.24/25.55/ /22.55/ /33.56/33.37 r.m.s.d bonds (Å) r.m.s.d angles ( o) Ramachandran Favoured (%) Allowed (%) Disallowed (%) * Values in parentheses correspond to the highest resolution shell. S14
15 PDB ID 5HRX 5II2 5IID Protein PB1(5) PB1(5) PB1(5) Compound Space group P P P Cell dimensions: a, b, c (Å) α, β, γ (deg) Resolution* (Å) (1.73) ( ) ( ) Unique observations* (1398) (16300) (6533) Completeness* (%) 97.8 (96.3) 99.0 (95.3) 99.3 (97.0) Redundancy* 5.6 (5.0) 6.3 (5.9) 4.6 (3.5) Rmerge* (0.893) (0.368) (0.784) I/σI* 17.3 (1.8) 9.1 (4.0) 10.4 (1.5) Refinement Resolution (Å) R work / R free (%) / / /28.1 Number of atoms (protein/other/water) 1810/44/ /57/ /40/49 B-factors (A 2 ) (protein/other/water) 32.71/29.78/ /22.88/ /45.64/41.39 r.m.s.d bonds (Å) r.m.s.d angles ( o) Ramachandran Favoured (%) Allowed (%) Disallowed (%) * Values in parentheses correspond to the highest resolution shell. Table S4. Data collection and refinement statistics. S15
16 Protein PB1(1) 0.3 ± ± ± ± ± ± 0.6 PB1(2) -0.4 ± ± ± ± ± ± 0.1 PB1(3) 0 ± ± ± ± ± ± 0.6 PB1(4) 0.1 ± ± ± ± ± ± 0.5 PB1(5) 0.7 ± ± ± ± ± ± 0.8 PB1(6) -0.1 ± ± ± ± ± ± 0.3 SMARCA 2A 0.4 ± ± ± ± ± ± 0.2 SMARCA 2B -0.1 ± ± ± ± ± ± 0.2 SMARCA 4A 0.5 ± ± ± ± ± ± 0.2 TAF1(1) ± ± 0.1 TAF1(2) ± ± 0.1 TAF1(1:2) ± ± 0 TAF1L(1) ± ± 0.4 TAF1L(2) ± ± 0.1 TAF1L(1:2) ± ± 0.3 BRD ± ± 0.1 BRD2(1) ± ± 0.6 BRD4(1) ± ± 0 BRD4(2) ± ± 0.1 Table S5. DSF assay summary. T m ( C) values are shown. The compounds were screened at 100µM while the protein was at 2.5µM. Compounds 9-12 were measured in triplicate on PB1 and SMARCA. 1 and 2 were measured in duplicate. S16
17 Protein Compound K d (µm) n G (kcal/mol) Η (kcal/mol) -Τ S (kcal/mol) PB1(5) PB1(5) PB1(5) PB1(5) PB1(5) PB1(3) 12 SMARCA2(2A) 12 BRD4(1) 12 No binding No binding No binding Table S6. Isothermal titration calorimetry summary. Protein (200µM) was titrated into compound solution (15µM) at 15 C. S17
18 Figure S1. The buried water molecule that is not displaced upon binding of 9 in PB1(5) is stabilized by an extended network of H-bonds through surrounding residues such as the sidechain of Y696, the backbone carbonyls of M704 and M731 as well as the carbonyl of 9. S18
19 S19
20 Figure S2. Compound 12 slightly reduces viability of 1BR-hTERT human fibroblast cells. (A) Viability curve for 1BR-hTERT cells treated with DMSO or 12. (B) Viability graph for cells as in (A) treated with DMSO or 2. (C) Cells treated with DMSO or 12 were processed for chromatin fractionation as outlined in the experimental procedures. Samples were blotted for PB1, α-tubulin or CENPA as indicated. (D) Viability curve for U2OS PB1 knock-out cells treated with 2 (upper graph) or 12 (lower graph) in presence of mitomycin C (MMC). S20
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