Supporting Information (SI)

Online Resource

Title: Digging into the deep pocket: in silico approaches to the design of

specific Type II kinase inhibitors

Authors: Daniel Mucs, Richard A. Bryce and Pascal Bonnet

Contents of SI: Title page S1 Figure 1S. (A) Non protonated N form and (B) Protonated Z form S2 of BIRB 796 (PDB ID: 1KV2)

Table 1S: List of 55 structures analysed, designation S3 as DFG-in/out, crystal structure code/resolution Table 2S. PDB accession codes of Type I/kinase complexes used S5 Table 3S: Geometric parameters for 55 Type II S6 crystal structures: angles  in degrees and distances d in Å. Table 4S. Description of pharmacophore models S7 Table 5S. Comparison of retrieval of Type I and Type II inhibitors S8 (%) from Amide and Urea datasets.

Table 6S. Specificity (Sp) and Selectivity (Se) values for S9 pharmacophore queries in screening Type II molecules from Amide and Urea datasets.

Table 7S. Average specificity (Sp), Selectivity (Se) and roc scores S10 for a given conformer generator or pharmacophore query in screening Type II molecules from Amide and Urea datasets.

Table 8S. Type I inhibitors commonly not filtered out and Type II S11 molecules commonly not picked up by any of the pharmacophore queries used (Q2, Q4, Q7)

Table 9S: Geometric analysis of four recent DFG- S13 out crystal structures, code/resolution List of references S14

S1 Figure 1S. (A) Neutral N form and (B) Protonated Z form of BIRB796 (PDB ID:

O O N H CH3 N CH3 CH3 CH3 CH3 O CH O 3 O N O N N N N H H N N N H H

CH (A) 3 (B) CH3

S2 Table 1S: List of 55 structures analysed, designation as DFG-in/out, crystal structure code/resolution (Å)

PDB Protein Ligand Name Res Ref code 1FPU c-Abl Imatinib (STI-571) 2.40 1 Analogue 1IEP c-Abl Imatinib (STI-571) 2.10 2 1KV1 p38 Fragment of BIRB796 2.50 3 1KV2 p38 BIRB796 2.80 3 1OPJ c-Abl Imatinib (STI-571) 1.75 4 1T46 c-Kit Imatinib (STI-571) 1.60 5 1UWH B-RAF Sorafenib (BAY439006) 2.95 6 1UWJ B-RAF (V599E) Sorafenib (BAY439006) 3.50 6 1W82 p38 alpha Fragment of BIRB796 2.20 7 1W83 p38 alpha Astex Compound 2.50 7 1WBN p38 alpha Astex Compound 2.40 7 1WBS p38 alpha Astex Compound 1.80 7 1WBT p38 alpha Astex Compound 2.00 7 1WBV p38 alpha Astex Compound 2.00 7 1YWN Vegfr2 (E990V) 4-amino-furo[2,3- 1.71 8 d]pyrimidine 2BAJ p38 alpha pyrazolourea 2.25 9 2BAK p38 alpha MPAQ 2.20 9 2E2B c-Abl INNO-406 2.20 10 2HIW Abl Scripps Compound 2.20 11 2HYY Abl Imatinib (STI-571) 2.40 12 2HZ0 Abl NVP-AEG082 2.10 12 2HZN Abl NVP-AFG210 2.70 12 2OFV Lck aminoquinazoline 1 2.00 13 2OG8 Lck aminoquinazoline 36 2.30 13 2OH4 Vegfr2 (E990V) benzimidazole-urea 2.05 14 2OIQ c-Src Imatinib (STI-571) 2.07 15 2OO8 Angiopoietin-1 receptor(Kinase domain) Triazine Derivative 2.20 16 2OSC Tie-2 pyridinyl pyrimidine 2.80 16 2P2I Vegfr2 (C817A, E990V) nicotinamide 2.40 17 2P4I Tie-2 2-(Pyridin-2-yl)-1,3,5- 2.50 17 triazine 2PL0 Lck Imatinib (STI-571) 2.80 18 2PUU p38 1-(5-tert-Butyl-2-p- 2.50 N/A tolyl-2H-pyrazol-3-yl)- 3-[4-(6-morpholin-4- ylmethyl-pyridin-3- yl)naphthalen-1-yl]urea 2QU5 Vegfr2 (C817A, V916T, E990V) benzimidazole 2.95 19 2QU6 Vegfr2 (C817A, V916T, E990V) benzoxazole 2.10 19 2RL5 Vegfr2 (C817A, V916T, E990V) 2,3-dihydro-1,4- 2.65 20 benzoxazine 3B8Q Vegfr2 (C817A, V916T, E990V) naphthamide 2.75 21 3BE2 Vegfr2 (C817A, V916T, E990V) benzamide 1.75 21 3BV3 p38 alpha n/a 2.59 22 3C1X Hegfr (Y1194F, Y1234F, Y1235D, Pyrrolotriazine 2.17 23 V1272L) 3CE3 Hegfr (Y1194F, Y1234F, Y1235D, Pyrrolopyridinepyridone 2.40 24 V1272L) 3CP9 Vegfr2 (C817A, V916T, E990V) pyridone 2.50 25 3CPB Vegfr2 (E817A, V916T, E990V) bisamide 2.70 25 3CPC Vegfr2 (C817A, V916T, E990V) pyridone 2.40 25 3CS9 c-Abl Nilotinib 2.21 26 3CTH Hegfr (Mutation: YES) aminopyridine 2.30 27 S3 3CTJ Hegfr (Mutation: YES) aminopyridine 2.50 27 3CTQ p38 1-o-tolyl-1,2,3-triazole- 1.95 28 4-carboxamide 3D83 p38 biphenyl amide 1.90 29 3DKO epha7 alw-ii-49-7 2.00 N/A 3DTW Vegfr2 (C817A, V916T, E990V) benzisoxazole 2.90 30 3DZQ EphA3 AWL-II-38.3 1.75 N/A 3EL7 c-Src pyrazolopyrimidine 3 2.80 31 3EL8 c-Src pyrazolopyrimidine 5 2.30 31 3F3T c-Src (S345C) RL38 2.50 32 3F3U c-Src (S345C) RL37 2.50 32

S4 Table 2S. PDB accession codes of Type I/kinase complexes used in this study.

Type I inhibitor/kinase complexes

1BX6,1GIH,1GIJ,1OIQ,1Q5K,1Q8T,1RE8,1REJ,1REK,1SVE,1SVG, 1SVH,1VEB,1VYW,1VYZ,1XBB,1XH4,1XH5,1XH6,1XH7,1XH8,1 XHA,1Y57,1Z5M,1ZYJ,1ZYS,2B1P,2B55,2C0I,2C0O,2C0T,2E9N,2 E9P,2EXC,2F4J,2FGI,2GMX,2GQG,2GU8,2H96,2H9V,2JAM,2JAV, 2JKK,2NP8,2NRU,2O2U,2OJI,2OJJ,2OK1,2OWB,2PE2,2PVN,2R64, 2RG5,2RG6,2RKU,2VGP,2VRX,2VTI,2VTL,2VTN,2VTO,2VTP,2V TQ,2VTT,2VU3,2VX3,2YWP,2ZB0,2ZB1,2ZDU,3B2W,3B8Q,3B8R, 3BI6,3BX5,3CG2,3CGO,3D14,3D7Z,3DB6,3E7O

S5 Table 3S: Geometric parameters for 55 Type II crystal structures: angles  in degrees and distances d1 – d3 (d1 – d3 refer to Asp381 O…N ligand, Glu286 N…OC ligand, Met318 N…Tyr253 Orespectively) in Å. PDB code q a b d 1 d 2 d 3 1FPU 117.24 89.54 32.86 3.14 3.09 8.95 1IEP 124.27 89.00 25.00 2.90 3.00 8.80 1KV1 81.35 3.05 2.76 22.10 1KV2 128.10 65.93 93.97 2.89 2.98 16.48 1OPJ 129.57 74.78 18.59 2.94 2.80 9.06 1T46 133.88 79.86 13.76 3.08 2.86 18.50 1UWH 128.37 86.80 80.80 3.14 3.00 17.45 1UWJ 126.34 75.30 65.27 3.37 3.06 17.55 1W82 70.77 2.78 3.04 23.80 1W83 110.98 88.11 59.80 2.88 3.12 13.20 1WBN 113.57 79.98 65.83 3.22 2.94 22.72 1WBS 105.78 67.09 19.48 2.90 3.01 22.58 1WBT 110.40 72.27 10.78 2.98 3.23 22.44 1WBV 68.74 2.86 3.07 18.43 1YWN 123.88 58.62 7.86 3.07 2.85 19.69 2BAJ 71.80 2.89 3.00 24.63 2BAK 104.94 80.90 72.90 3.13 2.80 20.16 2E2B 120.33 79.80 22.00 2.87 2.90 8.72 2HIW 103.58 76.00 38.30 2.89 3.45 9.63 2HYY 126.28 72.77 30.07 2.98 3.09 8.95 2HZ0 115.99 70.36 51.89 2.86 2.95 17.32 2HZN 121.64 74.73 55.35 2.75 2.87 17.57 2OFV 116.15 80.77 40.74 2.68 2.88 24.33 2OG8 118.16 88.27 72.10 2.95 3.16 24.51 2OH4 126.44 79.30 24.10 2.89 2.81 21.37 2OIQ 119.88 77.19 15.23 2.82 2.89 24.53 2OO8 124.92 88.50 40.12 2.99 2.93 2OSC 120.87 79.86 40.70 2.75 3.03 2P2I 114.58 76.39 75.42 2.81 2.87 16.04 2P4I 120.92 79.47 27.79 2.85 6.57 2PL0 117.79 70.91 18.38 2.95 2.86 25.04 2PUU 105.66 62.03 74.84 3.40 3.04 2QU5 131.74 74.60 51.10 3.06 2.86 15.54 2QU6 142.95 79.00 48.10 3.05 2.93 2RL5 116.04 73.88 64.55 2.70 3.20 3B8Q 124.05 89.90 78.54 2.83 3.34 22.48 3BE2 121.68 84.53 38.54 2.95 2.86 15.39 3BV3 118.41 72.32 42.23 3.33 2.42 22.47 3C1X 130.16 87.78 21.72 2.91 2.63 23.30 3CE3 119.68 88.73 16.47 2.86 22.85 3CP9 118.83 74.74 51.49 2.98 3CPB 120.60 66.89 55.63 2.76 2.63 3CPC 125.70 59.94 46.14 2.87 3CS9 123.10 82.06 24.52 3.08 2.99 9.19 3CTH 123.34 82.94 20.92 2.74 3.02 22.41 3CTJ 125.85 82.51 61.71 4.38 2.89 18.03 3CTQ 119.71 82.51 72.51 2.83 2.97 7.73 3D83 122.07 73.73 62.30 3.13 2.85 23.09 3DKO 9.68 2.90 2.75 20.50 3DTW 119.97 89.84 34.95 2.93 3.30 3DZQ 127.53 83.79 39.07 3.07 2.91 7.98 3EL7 125.39 69.70 10.84 3.14 3.52 16.49 3EL8 130.87 52.72 5.86 3.49 3.58 16.43 3F3T 76.17 2.87 2.52 23.79 3F3U 62.85 2.71 2.82 23.24 Average 120.78 77.74 45.97 3.0 3.03 18.19 STDEV 7.88 8.07 23.61 0.3 0.56 5.56 Median 120.90 79.15 47.12 2.9 2.95 18.50

S6 Table 4S. Description of pharmacophore models

Model Description

Q2 Six features: (1) a hydrogen bond donor (diameter=1.65 Å) and (2) hydrogen bond acceptor (diameter=0.91 Å) in HAHD, (3) an essential aromatic or hydrophobic feature of 1.33 Å diameter in HM region, (4) an essential aromatic or hydrophobic feature (diameter=1.82 Å) in the linker region, (5) an essential acceptor (diameter=1.26 Å) in HRB region and (6) an optional hydrogen bond acceptor or hydrophobic feature (diameter=1.53 Å) between HRB and linker region One grouped excluded volume constraint in proximity of hydrogen bond donor feature of HAHD.

Q4 Six features as above; features 3, 4 and 5 were marked essential One grouped excluded volume constraint (hinge region residues).

Q7 Six features as above with no features marked as essential. Three excluded grouped volume constraints (residue Glu286, the DFG motif residues and hinge region residues)

S7 Table 5S. Comparison of retrieval of Type I and Type II inhibitors (%) from Amide

and Urea datasets.

Macromodel MOE Omega SPE Query Type I Type II Type I Type II Type I Type II Type I Type II

Amide Q2 44.0 90.3 52.0 90.3 52.0 87.1 52.0 93.5 Q4 26.7 90.3 34.7 83.9 32.0 83.9 32.0 90.3 Q7 18.7 87.1 28.0 80.6 24.0 77.4 18.7 80.6

Q2 37.5 91.7 50.0 91.7 50.0 83.3 50.0 75.0 Q4 50.0 83.3 25.0 58.3 25.0 75.0 37.5 66.7 Q7 25.0 75.0 12.5 58.3 25.0 75.0 25.0 58.3

S8 Table 6S. Specificity (Sp) and Selectivity (Se) values for pharmacophore queries in screening Type II molecules from Amide and Urea datasets.

Macromodel MOE Omega SPE Sp/Se Amide Urea Amide Urea Amide Urea Amide Urea

Q2 Sp 0.56 0.63 0.48 0.50 0.48 0.50 0.48 0.63 Se 0.91 0.92 0.91 0.92 0.89 0.86 0.94 0.80 Q4 Sp 0.73 0.50 0.65 0.75 0.68 0.75 0.68 0.63 Se 0.91 0.86 0.86 0.71 0.86 0.80 0.91 0.75 Q7 Sp 0.81 0.75 0.72 0.88 0.76 0.75 0.81 0.75 Se 0.89 0.80 0.84 0.71 0.82 0.80 0.84 0.71

S9 Table 7S. Average specificity (Sp), Selectivity (Se) and roc scores for a given conformer generator or pharmacophore query in screening Type II molecules from

Amide and Urea datasets.

Amide Urea Sp Se roc Sp Se roc Macromodel 0.90 0.73 0.80 0.85 0.66 0.73 MOE 0.86 0.64 0.73 0.76 0.75 0.70 Omega 0.85 0.67 0.74 0.82 0.69 0.72 SPE 0.88 0.70 0.77 0.74 0.69 0.65 Q2 0.50 0.91 0.70 0.57 0.88 0.70 Q4 0.69 0.89 0.78 0.66 0.78 0.69 Q7 0.78 0.85 0.80 0.78 0.76 0.73

S10 Table 8S. Type I inhibitors commonly not filtered out and Type II molecules commonly not picked up by any of the pharmacophore queries used (Q2, Q4, Q7)

Type I not Type II not Type I not filtered filtered picked up Type II not picked up (Amide) (Urea) (Amide) (Urea)

N HN N

NH N HN O

NH HN CH3 HN HN CH3 CH O CH 3 O H C N 3 N HN 3 N CH3 O N N O N F H3C Cl N H CH N O 3 F H N F H

3BV3 3DB6 2P2I 1KV1

N O CH3 O N NH N

N NH2 Br H N HN

HN NH O F O HN O NH F

H3C CH3 N F F

O NH2 O F

1Z5M 1WBV 1YWN

N N H N

H C N N S 3 H O H3C

H N CH3 H3C O O HN N NH

S11 2JKK

NH CH 3 CH H 3 CH3 N N

H3C H3C O O

O N F F H F HN HN F

HN N N

N HN H

S12 Table 9S: Geometric parameters for four recent Type II crystal structures: angles  in degrees and distances d1 – d2 in Å (see Table 3S for definition of d1 and d2).

PDB code kinase ligand d1 d2   

3F3V c-Src RL45 2.43 2.95 73.19 146.21 73.36

3FZS PYK2 BIRB796 2.96 2.76 46.24 135.51 45.92

3GCU P38 MAP RL48 3.22 2.75 61.67 124.99 68.09

3II5 B-RAF Pyrazolo pyrimidine 2.90 3.10 80.76 111.52 83.56

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