Journal: J.Med.Chem. / Year: 2020 Title: Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H -isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a ]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual- ...Title: Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H -isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a ]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "Dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis. Authors: Larsen, J. / Lambert, M. / Pettersson, H. / Vifian, T. / Larsen, M. / Ollerstam, A. / Hegardt, P. / Eskilsson, C. / Laursen, S. / Soehoel, A. / Skak-Nielsen, T. / Hansen, L.M. / Knudsen, N.O. ...Authors: Larsen, J. / Lambert, M. / Pettersson, H. / Vifian, T. / Larsen, M. / Ollerstam, A. / Hegardt, P. / Eskilsson, C. / Laursen, S. / Soehoel, A. / Skak-Nielsen, T. / Hansen, L.M. / Knudsen, N.O. / Eirefelt, S. / Sorensen, M.D. / Stilou, T.G. / Nielsen, S.F.
Mass: 18.015 Da / Num. of mol.: 1344 / Source method: isolated from a natural source / Formula: H2O
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Details
Has ligand of interest
Y
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Experimental details
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Experiment
Experiment
Method: X-RAY DIFFRACTION / Number of used crystals: 1
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Sample preparation
Crystal
Density Matthews: 2.7 Å3/Da / Density % sol: 54.42 %
Crystal grow
Temperature: 277 K / Method: vapor diffusion, sitting drop Details: Protein stored at 20.6 mg/mL in a storage buffer of 50 mM NaCl, 20 mM Tris HCl (pH 7.5), 1 mM TCEP, 1 mM EDTA. Reservoir was 0.1 M HEPES (pH 7.5), 19% PEG3350, 25% ethylene glycol, 5% 2- ...Details: Protein stored at 20.6 mg/mL in a storage buffer of 50 mM NaCl, 20 mM Tris HCl (pH 7.5), 1 mM TCEP, 1 mM EDTA. Reservoir was 0.1 M HEPES (pH 7.5), 19% PEG3350, 25% ethylene glycol, 5% 2-propanol, 5% glycerol. Drops were microseeded. Apo crystals were soaked with 0.8 mM LEO39652A for 3 days.
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Data collection
Diffraction
Mean temperature: 100 K / Serial crystal experiment: N
Resolution: 1.6→79.939 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.966 / SU B: 1.751 / SU ML: 0.057 / Cross valid method: THROUGHOUT / ESU R: 0.071 / ESU R Free: 0.074 Details: Hydrogens were added in their riding positions for refinement but removed for deposition.
Rfactor
Num. reflection
% reflection
Rfree
0.1918
11947
5.083 %
Rwork
0.1616
223091
-
all
0.163
-
-
obs
-
235038
99.938 %
Solvent computation
Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parameters
Biso mean: 27.135 Å2
Baniso -1
Baniso -2
Baniso -3
1-
0.009 Å2
-0 Å2
0 Å2
2-
-
-0.008 Å2
-0 Å2
3-
-
-
-0.001 Å2
Refinement step
Cycle: LAST / Resolution: 1.6→79.939 Å
Protein
Nucleic acid
Ligand
Solvent
Total
Num. atoms
10650
0
260
1344
12254
Refine LS restraints
Refine-ID
Type
Dev ideal
Dev ideal target
Number
X-RAY DIFFRACTION
r_bond_refined_d
0.01
0.013
11467
X-RAY DIFFRACTION
r_bond_other_d
0.001
0.017
10607
X-RAY DIFFRACTION
r_angle_refined_deg
1.59
1.635
15589
X-RAY DIFFRACTION
r_angle_other_deg
1.521
1.584
24663
X-RAY DIFFRACTION
r_dihedral_angle_1_deg
5.423
5
1398
X-RAY DIFFRACTION
r_dihedral_angle_2_deg
31.745
23.783
608
X-RAY DIFFRACTION
r_dihedral_angle_3_deg
13.454
15
2036
X-RAY DIFFRACTION
r_dihedral_angle_4_deg
16.941
15
54
X-RAY DIFFRACTION
r_chiral_restr
0.09
0.2
1505
X-RAY DIFFRACTION
r_gen_planes_refined
0.009
0.02
13110
X-RAY DIFFRACTION
r_gen_planes_other
0.001
0.02
2240
X-RAY DIFFRACTION
r_nbd_refined
0.231
0.2
2916
X-RAY DIFFRACTION
r_symmetry_nbd_other
0.18
0.2
10115
X-RAY DIFFRACTION
r_nbtor_refined
0.169
0.2
5822
X-RAY DIFFRACTION
r_symmetry_nbtor_other
0.082
0.2
4379
X-RAY DIFFRACTION
r_xyhbond_nbd_refined
0.242
0.2
1093
X-RAY DIFFRACTION
r_symmetry_xyhbond_nbd_other
0.136
0.2
2
X-RAY DIFFRACTION
r_metal_ion_refined
0.024
0.2
1
X-RAY DIFFRACTION
r_symmetry_nbd_refined
0.217
0.2
36
X-RAY DIFFRACTION
r_nbd_other
0.243
0.2
135
X-RAY DIFFRACTION
r_symmetry_xyhbond_nbd_refined
0.233
0.2
47
X-RAY DIFFRACTION
r_mcbond_it
2.157
2.589
5447
X-RAY DIFFRACTION
r_mcbond_other
2.157
2.589
5448
X-RAY DIFFRACTION
r_mcangle_it
2.804
3.871
6856
X-RAY DIFFRACTION
r_mcangle_other
2.804
3.871
6857
X-RAY DIFFRACTION
r_scbond_it
3.319
2.959
6020
X-RAY DIFFRACTION
r_scbond_other
3.319
2.959
6021
X-RAY DIFFRACTION
r_scangle_it
4.972
4.291
8709
X-RAY DIFFRACTION
r_scangle_other
4.971
4.291
8710
X-RAY DIFFRACTION
r_lrange_it
6.874
33.135
14187
X-RAY DIFFRACTION
r_lrange_other
6.455
32.208
13732
LS refinement shell
Resolution (Å)
Rfactor Rfree
Num. reflection Rfree
Rfactor Rwork
Num. reflection Rwork
Refine-ID
% reflection obs (%)
1.6-1.642
0.3
931
0.302
16310
X-RAY DIFFRACTION
99.8552
1.642-1.687
0.307
867
0.288
15919
X-RAY DIFFRACTION
99.8751
1.687-1.735
0.274
810
0.256
15522
X-RAY DIFFRACTION
99.9572
1.735-1.789
0.259
769
0.235
15165
X-RAY DIFFRACTION
99.9498
1.789-1.847
0.245
793
0.215
14570
X-RAY DIFFRACTION
99.9805
1.847-1.912
0.219
778
0.193
14121
X-RAY DIFFRACTION
99.9597
1.912-1.984
0.22
753
0.179
13633
X-RAY DIFFRACTION
99.875
1.984-2.065
0.191
692
0.165
13212
X-RAY DIFFRACTION
99.9641
2.065-2.157
0.179
636
0.154
12661
X-RAY DIFFRACTION
99.9774
2.157-2.262
0.182
625
0.145
12132
X-RAY DIFFRACTION
99.9922
2.262-2.385
0.176
614
0.143
11574
X-RAY DIFFRACTION
99.9918
2.385-2.529
0.18
580
0.137
10870
X-RAY DIFFRACTION
100
2.529-2.704
0.178
541
0.133
10288
X-RAY DIFFRACTION
99.7513
2.704-2.92
0.166
541
0.134
9520
X-RAY DIFFRACTION
99.9305
2.92-3.199
0.171
453
0.141
8903
X-RAY DIFFRACTION
99.9893
3.199-3.576
0.169
408
0.144
8047
X-RAY DIFFRACTION
99.9882
3.576-4.128
0.174
402
0.147
7093
X-RAY DIFFRACTION
100
4.128-5.053
0.16
345
0.14
6043
X-RAY DIFFRACTION
99.9843
5.053-7.135
0.249
261
0.209
4762
X-RAY DIFFRACTION
99.9801
7.135-79.939
0.193
148
0.159
2748
X-RAY DIFFRACTION
99.7245
+
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