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The title compound, abbreviated as 5'Thio­methylImmA, is a potent inhibitor of methyl­thio­adenosine phospho­rylase [Singh et al. (2004). Biochemistry, 43, 9-18]. The synchrotron study reported here shows that the hydro­chloride salt crystallizes with two independent, nearly superimposable, dications as a monohydrate with formula 2C12H19N5O2S2+·4Cl-·H2O. Hydro­gen bonding utilizing the H atoms of the dication is found to favour certain mol­ecular conformations in the salt, which are significantly different from those found as bound in the enzyme. Ligand docking studies starting from either of these dications or related neutral structures successfully place the conformationally revised structures in the enzyme active site but only under particular hydrogen-bonding and mol­ecular flexibility criteria. Density functional theory calculations verify the energy similarity of the independent cations and confirm the significant energy cost of the required conformational change to the enzyme bound form. The results suggest that using crystallographically determined free ligand coordinates as starting parameters for modelling may have serious limitations.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270110037121/fg3191sup1.cif
Contains datablocks global, I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270110037121/fg3191Isup2.hkl
Contains datablock I

CCDC reference: 804121

Comment top

The title compound, (I), a potent inhibitor of methylthioadenosine phosphorylase (MTAP), was prepared by Evans et al. (2004) as part of a synthesis program aimed at anticancer lead compounds. The structure and stereochemistry were established prior to its subsequent definition in the active site of the enzyme [Protein Data Bank (PDB) ID code 1K27 used hereafter), as reported by Singh et al. (2004). This report notes the details of the crystal structure of the double-protonated (dication) chloride salt, which includes a water of crystallization, (I). Additional information about the computational docking of the compound in the enzyme using the 1K27 coordinates has been determined using the docking program GOLD (Jones et al., 1997; Nissink et al., 2002). The results are discussed in the light of the different molecular conformations found for the two independent molecules as compared with that observed bound in the MTAP enzyme structure and the relative energies calculated by DFT (density functional theory) methods (ADF2009.01, 2009).

The structure contains two independent dicationic C12H19N5O2S molecules, four chloride anions and one water molecule of crystallization. These two molecule conformations (molecules 1 and 2 hereafter) have atom labels related by the numerical addition of 10 (e.g. N3 and N13, see Fig. 1).

The crystal packing can be described as a one-dimensional array built along the b screw axis, with some links along the c axis, utilizing a network of hydrogen bonds: N—H···Cl, (C)O—H···Cl, O(water)—H···Cl, O(water)—H···N and one O—H···S (Table 1, Fig. 2). There are no strong links between the lattices, with the methylthio (e.g. C6', S1, C5') interactions defining the spacing up the a cell axes. The basic building blocks consist of D11(2) moiety types (Bernstein et al., 1995) which build to larger D22 forms mainly; there are only a few examples of other types e.g. bifurcated binding which generate the R12(7) (entries 7 and 8, Table 1) and R12(8) (entries 5 and 10, Table 1) motifs. The key hydrogen bonds that promote the observed conformations in both molecules, as distinct from that found in the enzyme (Table 2), involve the additional H atoms that give the overall 2+ charge (namely on atoms N3, N13, N1' and N11'). These latter atoms form inter-linking bonds (see entries 4 and 14, and 5 and 12 in Table 1) as shown in Fig. 3 which could not form if the conformations were as found in the enzyme.

It is common practice to take X-ray-diffraction-derived molecular parameters as starting models for ligand docking studies. In this case it was of some interest to determine if the docking computations using the software package GOLD could rotate the two rings ~130° about the C1'—C9 bond to reproduce the observed conformation in the enzyme (see Table 2, Fig. 4). The initial test starting with the found 1K27 ligand coordinates (`ligand A': with H atoms in calculated positions) without using any constraints was successful. By contrast, neither the dication nor the neutral molecule based on molecules 1 and 2 gave any correctly docked solutions. Only when the pyrrolidine ring was allowed to flex, using the flip ring corners option, did any correct solutions appear: both the dication-based coordinates and the `ligand A' sets gave some good matches but not with the highest docking scores.

To obtain the closest matches with the observed ligand A in 1K27, coupled with the highest docking scores for all the models, required three constraints: specifying which enzyme atoms had hydrogen bonds (but not which ligand atoms were involved), flipping the pyramidal N atom in the pyrrolidine ring and exploring the ring conformations. Using GOLD's CHEMSCORE and CHEMPLP scoring regimes gave the highest numerical score for the (starting coordinate) `ligand A' set, the neutral and dication (molecule 1)-based coordinates scoring somewhat less, but correctly in terms of matching the ligand conformation and position in 1K27. There was some variation in final positioning of the terminal S-methyl group in the dication run (Table 2, DiMo1 column) as indicated in Fig. 5 and Table 2.

These results led us to calculate the molecular energies using DFT methods (ADF2009.01, 2009). The BLYP functional formed from the combination of the local density approximation (LDA) parameterization by Vosko et al. (1980), VWN5, with the B88 exchange gradient correction (Becke, 1988) and the LYP correlation gradient correction (Lee et al., 1988) were used. The basis set used was triple-zeta quality for all valence orbitals and included two sets of polarization functions on each atom (Van Lenthe & Baerends, 2003). The polarization functions are '1p1d' on the H atoms and '1 d1f' on the C, N and O atoms. The positions of the heavy atoms were frozen at the values taken from the crystal or docked structures but the coordinates of the H atoms were allowed to relax. The energy differences found, from the specified starting models, relative to the docked conformation are shown in Table 2 (final DFT calculated geometries are not given).

The similarity of results for the molecule 1 and 2 conformations in geometry and energy [difference 6 kJ mol-1 (1.24 kcal mol-1)] gives credence to the calculations, which show that the enzyme-bound `ligand A' dication conformation has much higher energy (~253 kJ mol-1). The energy required to distort the molecule to its docking geometry must be made up by energy gained through favorable interactions with the enzyme. A phosphate species is well placed to strongly interact with the cation. Furthermore, the protein structure and docking studies suggest that when in place the cation will form several hydrogen bonds with its host: four such P—O···H—O,N interactions are observed. Together, these bonds should be able to stabilize the cation in its docked conformation. In the case of the neutral molecule, the docked conformation is found to be lower in energy by 62 kJ mol-1 than the conformation suggested by the 1K27 ligand A crystal structure.

These latter results strongly suggest that docking of the free ligand molecules 1 and 2 in the 1K27 enzyme (and by analogy for other similar cases) must include hydrogen-bonding interactions. This was also indicated by the final (successful) criteria applied in the GOLD docking runs. A sobering corollary to this finding is that crystallographically determined free ligand conformations may not be reproduced in enzyme binding sites, which may limit their potential as starting models for drug discovery.

Related literature top

For related literature, see: Becke (1988); Bernstein et al. (1995); Evans et al. (2004); Jones et al. (1997); Lee et al. (1988); Nissink et al. (2002); Singh et al. (2004); Vosko et al. (1980).

Experimental top

The compound was prepared as reported for compound 2 by Evans et al. (2004).

Refinement top

The N—H distances of two types (viz. N3, N7, N13, N17 and N6, N16) were restrained to be equal [SHELXL (Sheldrick, 2008) SADI function with effective standard deviation of 0.03 Å]. The methyl H atoms were constrained to an ideal geometry (C—H = 0.98 Å) but were allowed to rotate freely about the adjacent C—C bond. The hydroxyl H atoms were constrained to an ideal geometry (O—H = 0.84 Å) with Uiso(H) = 1.2Ueq(O), but were allowed to rotate freely about the adjacent C—O bond. All other H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with C—H distances of 1.00 (primary), 0.99 (methylene) or 0.95 (aromatic) Å. All H atoms were refined with Uiso(H) = 1.2Ueq(parent atom).

Computing details top

Data collection: DENZO (Otwinowski & Minor, 1997); cell refinement: DENZO (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. Diagram of the asymmetric unit contents of (I) with two independent cations, shown with 50% displacement ellipsoids (Farrugia, 1997). H atoms have arbitrary radii.
[Figure 2] Fig. 2. A Mercury stereo packing view (Macrae et al., 2008) of the cell highlighting the separated lattices along the b axis. H atoms have been omitted for clarity. Some of the atoms involved in hydrogen bonds are shown in ball mode (see Table 1). Symmetry code: (i) 1 - x, y - 1/2, 1/2 - z.
[Figure 3] Fig. 3. Key hydrogen-bonding interactions in (I), see text; the asymmetric unit is shown with selected hydrogen bonds as dotted lines (Farrugia, 1997). H atoms have arbitrary radii; other atoms are shown with 50% displacement ellipsoids.
[Figure 4] Fig. 4. 9-Deazaadenin-9-yl-overlapped stereo view of molecule 1 (thick bonds) and the final docked molecule DiMo1 (Table 2, thin bonds) illustrating the conformational differences (Mercury, Macrae et al., 2008).
[Figure 5] Fig. 5. Overlapped views of GOLD CHEMSCORE docking models (see text): black, ligand A (as in 1K27 with added H atoms); red, docked result starting with ligand A positions; blue, starting with molecule 1 (DiMo1).
Bis[(1S)-1,4-azanediyl-1-(9-deazaadenin-9-yl)-1,4-dideoxy-5- methylsulfanyl-D-ribitol] tetrakis(hydrochloride) monohydrate top
Crystal data top
2C12H19N5O2S2+·4Cl·H2OF(000) = 1576
Mr = 754.58Dx = 1.539 Mg m3
Orthorhombic, P212121Synchrotron radiation, λ = 0.92014 Å
Hall symbol: P 2ac 2abθ = 3.8–26.5°
a = 7.0080 (14) ŵ = 1.05 mm1
b = 18.717 (4) ÅT = 100 K
c = 24.825 (5) ÅPlate, colourless
V = 3256.3 (11) Å30.23 × 0.20 × 0.15 mm
Z = 4
Data collection top
ADSC Quantum CCD Detector
diffractometer
3821 reflections with I > 2σ(I)
Si111 monochromatorRint = 0.000
Detector resolution: 4000 pixels mm-1θmax = 29.6°, θmin = 1.8°
ϕ scanh = 66
3864 measured reflectionsk = 1919
3864 independent reflectionsl = 2525
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.027H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.066 w = 1/[σ2(Fo2) + (0.P)2 + 2.896P]
where P = (Fo2 + 2Fc2)/3
S = 1.06(Δ/σ)max = 0.001
3864 reflectionsΔρmax = 0.40 e Å3
454 parametersΔρmin = 0.24 e Å3
12 restraintsAbsolute structure: Flack (1983), ???? Friedel pairs
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.03 (3)
Crystal data top
2C12H19N5O2S2+·4Cl·H2OV = 3256.3 (11) Å3
Mr = 754.58Z = 4
Orthorhombic, P212121Synchrotron radiation, λ = 0.92014 Å
a = 7.0080 (14) ŵ = 1.05 mm1
b = 18.717 (4) ÅT = 100 K
c = 24.825 (5) Å0.23 × 0.20 × 0.15 mm
Data collection top
ADSC Quantum CCD Detector
diffractometer
3821 reflections with I > 2σ(I)
3864 measured reflectionsRint = 0.000
3864 independent reflectionsθmax = 29.6°
Refinement top
R[F2 > 2σ(F2)] = 0.027H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.066Δρmax = 0.40 e Å3
S = 1.06Δρmin = 0.24 e Å3
3864 reflectionsAbsolute structure: Flack (1983), ???? Friedel pairs
454 parametersAbsolute structure parameter: 0.03 (3)
12 restraints
Special details top

Experimental. Crystal decay was monitored and corrected by the inter-frame analysis (DENZO: Otwinowski & Minor,1997).

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
Cl10.55979 (11)0.32882 (4)0.05394 (3)0.0173 (2)
Cl20.11689 (12)0.60238 (4)0.06993 (3)0.01837 (19)
Cl30.48675 (12)0.71937 (4)0.26035 (3)0.0221 (2)
Cl40.98911 (13)0.71774 (4)0.21636 (3)0.0244 (2)
S10.59682 (13)0.54848 (4)0.48204 (3)0.0197 (2)
O2'1.1834 (3)0.71312 (11)0.39562 (8)0.0206 (5)
H2O'1.23150.74790.41220.025*
O3'0.9786 (3)0.59735 (11)0.35863 (8)0.0195 (5)
H3O'1.09790.60080.35640.023*
N1'0.6702 (4)0.71542 (13)0.37482 (11)0.0140 (6)
H1N'0.617 (5)0.7453 (16)0.3985 (13)0.017*
H2N'0.611 (5)0.7137 (16)0.3455 (13)0.017*
N10.7641 (4)0.97655 (13)0.24214 (10)0.0166 (7)
N30.7974 (4)0.85403 (13)0.26189 (9)0.0156 (6)
H3N0.812 (5)0.8125 (13)0.2486 (12)0.019*
N60.8211 (4)1.06371 (14)0.30589 (11)0.0201 (7)
H6A0.833 (5)1.0948 (15)0.2822 (11)0.024*
H6B0.860 (5)1.0738 (17)0.3369 (10)0.024*
N70.8772 (4)0.94027 (13)0.38524 (10)0.0138 (6)
H7N0.880 (5)0.9794 (13)0.4007 (12)0.017*
C1'0.8664 (5)0.74539 (15)0.36206 (11)0.0152 (7)
H1'0.90860.72660.32630.018*
C2'0.9867 (5)0.71000 (16)0.40637 (11)0.0155 (7)
H2'0.95860.73260.44200.019*
C3'0.9140 (5)0.63388 (15)0.40564 (11)0.0141 (7)
H3'0.94980.60770.43930.017*
C4'0.6980 (5)0.64113 (15)0.40005 (11)0.0127 (7)
H4'0.64930.60380.37470.015*
C5'0.5877 (5)0.63705 (15)0.45291 (11)0.0148 (7)
H5A'0.45290.65040.44640.018*
H5B'0.64200.67180.47870.018*
C6'0.4043 (7)0.50575 (18)0.44716 (15)0.0395 (11)
H6A'0.28490.53110.45480.047*
H6B'0.39340.45610.45930.047*
H6C'0.42920.50670.40830.047*
C20.7630 (5)0.90827 (16)0.22861 (12)0.0184 (8)
H20.73540.89700.19210.022*
C40.8305 (4)0.86900 (15)0.31516 (11)0.0119 (7)
C50.8350 (4)0.94007 (15)0.33133 (11)0.0125 (7)
C60.8083 (5)0.99495 (15)0.29388 (12)0.0137 (7)
C80.8937 (5)0.87214 (15)0.40235 (12)0.0142 (7)
H80.92100.85840.43840.017*
C90.8651 (5)0.82491 (15)0.35997 (11)0.0129 (7)
S20.13315 (12)0.87798 (4)0.06431 (3)0.0192 (2)
O12'0.8105 (3)0.72051 (10)0.04478 (8)0.0166 (5)
H12O0.87010.68370.05440.020*
O13'0.6907 (3)0.83507 (10)0.10569 (8)0.0168 (5)
H13O0.78950.84000.08690.020*
N11'0.4061 (4)0.70763 (13)0.13602 (11)0.0135 (6)
H11A0.314 (5)0.6788 (17)0.1206 (12)0.016*
H11B0.385 (5)0.7048 (15)0.1711 (13)0.016*
N110.7402 (4)0.45557 (13)0.24352 (9)0.0139 (6)
N130.7216 (4)0.57741 (13)0.21988 (10)0.0145 (6)
H13N0.750 (5)0.6212 (13)0.2276 (12)0.017*
N160.6765 (4)0.36652 (14)0.18173 (10)0.0171 (7)
H61A0.651 (5)0.3518 (16)0.1503 (10)0.020*
H61B0.673 (5)0.3380 (15)0.2067 (11)0.020*
N170.6078 (4)0.48691 (13)0.10073 (10)0.0143 (6)
H17N0.600 (5)0.4500 (14)0.0820 (11)0.017*
C11'0.6048 (5)0.68262 (15)0.12097 (11)0.0129 (7)
H11'0.69900.70420.14650.016*
C12'0.6252 (5)0.71856 (15)0.06594 (11)0.0134 (7)
H12'0.53810.69470.03960.016*
C13'0.5544 (4)0.79442 (15)0.07684 (11)0.0132 (7)
H13'0.51570.81890.04270.016*
C14'0.3823 (5)0.78349 (15)0.11466 (11)0.0139 (7)
H14'0.39020.81810.14530.017*
C15'0.1870 (5)0.78941 (16)0.08794 (12)0.0168 (7)
H15A0.08800.77470.11410.020*
H15B0.18180.75590.05710.020*
C16'0.1406 (6)0.92665 (17)0.12637 (13)0.0308 (9)
H16A0.07930.89850.15480.037*
H16B0.07300.97210.12200.037*
H16C0.27370.93600.13620.037*
C120.7560 (5)0.52407 (16)0.25467 (12)0.0187 (8)
H120.79470.53670.29010.022*
C140.6696 (4)0.56097 (15)0.16816 (11)0.0109 (7)
C150.6584 (4)0.48961 (15)0.15404 (12)0.0115 (7)
C160.6895 (5)0.43535 (15)0.19256 (11)0.0121 (7)
C180.5854 (5)0.55487 (15)0.08232 (11)0.0139 (7)
H180.54970.56730.04660.017*
C190.6222 (4)0.60331 (15)0.12306 (11)0.0104 (7)
O1W0.3501 (4)0.58651 (13)0.32748 (9)0.0245 (6)
H1WA0.335 (5)0.5442 (18)0.3059 (14)0.029*
H2WA0.377 (6)0.6195 (19)0.3085 (14)0.029*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0234 (5)0.0125 (4)0.0160 (4)0.0001 (3)0.0001 (3)0.0006 (3)
Cl20.0210 (5)0.0126 (4)0.0215 (4)0.0011 (3)0.0033 (3)0.0003 (3)
Cl30.0320 (6)0.0196 (4)0.0146 (4)0.0029 (4)0.0022 (3)0.0023 (3)
Cl40.0273 (5)0.0207 (4)0.0251 (4)0.0020 (4)0.0023 (3)0.0033 (3)
S10.0290 (6)0.0134 (4)0.0166 (4)0.0005 (4)0.0014 (4)0.0029 (3)
O2'0.0208 (16)0.0166 (12)0.0244 (12)0.0011 (10)0.0016 (10)0.0041 (9)
O3'0.0233 (15)0.0147 (11)0.0204 (11)0.0036 (11)0.0052 (10)0.0045 (9)
N1'0.0199 (19)0.0114 (14)0.0106 (13)0.0038 (13)0.0019 (11)0.0004 (11)
N10.0188 (19)0.0163 (15)0.0148 (14)0.0004 (11)0.0055 (11)0.0005 (11)
N30.0215 (18)0.0092 (14)0.0159 (14)0.0013 (12)0.0022 (12)0.0001 (12)
N60.031 (2)0.0112 (16)0.0180 (15)0.0002 (13)0.0026 (13)0.0036 (12)
N70.0168 (17)0.0077 (14)0.0169 (15)0.0032 (12)0.0006 (12)0.0027 (11)
C1'0.021 (2)0.0101 (17)0.0148 (15)0.0013 (15)0.0029 (14)0.0014 (12)
C2'0.013 (2)0.0190 (17)0.0146 (16)0.0006 (15)0.0003 (13)0.0021 (13)
C3'0.024 (2)0.0081 (16)0.0108 (15)0.0031 (14)0.0010 (13)0.0023 (12)
C4'0.019 (2)0.0079 (15)0.0112 (15)0.0002 (14)0.0013 (13)0.0021 (12)
C5'0.018 (2)0.0124 (16)0.0137 (15)0.0012 (14)0.0005 (13)0.0023 (12)
C6'0.061 (3)0.025 (2)0.032 (2)0.021 (2)0.017 (2)0.0056 (16)
C20.022 (2)0.020 (2)0.0133 (16)0.0009 (15)0.0003 (13)0.0025 (14)
C40.009 (2)0.0122 (17)0.0148 (17)0.0042 (14)0.0005 (12)0.0003 (13)
C50.006 (2)0.0147 (17)0.0167 (18)0.0025 (13)0.0010 (12)0.0002 (13)
C60.008 (2)0.0138 (18)0.0192 (18)0.0012 (13)0.0037 (13)0.0010 (13)
C80.0142 (19)0.0125 (17)0.0157 (16)0.0001 (14)0.0017 (14)0.0003 (13)
C90.012 (2)0.0096 (16)0.0177 (16)0.0049 (14)0.0002 (13)0.0016 (13)
S20.0239 (5)0.0153 (4)0.0182 (4)0.0030 (4)0.0027 (3)0.0011 (3)
O12'0.0149 (14)0.0150 (11)0.0199 (11)0.0034 (10)0.0025 (9)0.0038 (9)
O13'0.0147 (14)0.0134 (11)0.0223 (11)0.0049 (10)0.0011 (9)0.0023 (9)
N11'0.0157 (18)0.0130 (15)0.0118 (13)0.0002 (12)0.0033 (12)0.0021 (11)
N110.0192 (18)0.0120 (15)0.0104 (13)0.0022 (11)0.0037 (11)0.0002 (11)
N130.0223 (17)0.0088 (14)0.0124 (14)0.0000 (12)0.0051 (11)0.0025 (11)
N160.025 (2)0.0108 (16)0.0150 (15)0.0015 (13)0.0016 (12)0.0045 (11)
N170.0200 (17)0.0101 (14)0.0129 (14)0.0008 (12)0.0001 (12)0.0032 (10)
C11'0.014 (2)0.0115 (16)0.0132 (15)0.0003 (14)0.0018 (13)0.0014 (12)
C12'0.016 (2)0.0130 (16)0.0111 (15)0.0007 (14)0.0007 (13)0.0010 (12)
C13'0.016 (2)0.0118 (16)0.0121 (15)0.0008 (13)0.0023 (12)0.0010 (12)
C14'0.018 (2)0.0094 (15)0.0139 (15)0.0041 (15)0.0002 (13)0.0011 (12)
C15'0.019 (2)0.0119 (16)0.0189 (17)0.0008 (15)0.0014 (14)0.0015 (13)
C16'0.049 (3)0.0194 (19)0.0241 (19)0.0061 (18)0.0000 (17)0.0071 (14)
C120.023 (2)0.021 (2)0.0126 (17)0.0065 (15)0.0008 (13)0.0010 (14)
C140.008 (2)0.0122 (16)0.0123 (17)0.0026 (13)0.0038 (12)0.0023 (12)
C150.004 (2)0.0138 (17)0.0167 (18)0.0016 (13)0.0035 (12)0.0000 (13)
C160.008 (2)0.0129 (18)0.0158 (17)0.0031 (13)0.0032 (13)0.0027 (13)
C180.016 (2)0.0126 (17)0.0126 (16)0.0032 (14)0.0006 (13)0.0018 (13)
C190.0075 (19)0.0112 (16)0.0127 (16)0.0002 (14)0.0034 (12)0.0010 (12)
O1W0.0271 (17)0.0217 (13)0.0246 (13)0.0048 (12)0.0000 (10)0.0041 (10)
Geometric parameters (Å, º) top
S1—C6'1.792 (4)S2—C15'1.798 (3)
S1—C5'1.810 (3)O12'—C12'1.401 (4)
O2'—C2'1.405 (4)O12'—H12O0.8400
O2'—H2O'0.8400O13'—C13'1.416 (4)
O3'—C3'1.426 (3)O13'—H13O0.8400
O3'—H3O'0.8400N11'—C11'1.516 (4)
N1'—C1'1.519 (4)N11'—C14'1.525 (4)
N1'—C4'1.537 (4)N11'—H11A0.92 (3)
N1'—H1N'0.89 (3)N11'—H11B0.88 (3)
N1'—H2N'0.84 (3)N11—C121.316 (4)
N1—C21.321 (4)N11—C161.367 (4)
N1—C61.365 (4)N13—C121.342 (4)
N3—C21.331 (4)N13—C141.370 (4)
N3—C41.371 (4)N13—H13N0.87 (2)
N3—H3N0.85 (2)N16—C161.319 (4)
N6—C61.324 (4)N16—H61A0.85 (2)
N6—H6A0.83 (2)N16—H61B0.82 (2)
N6—H6B0.84 (2)N17—C181.361 (4)
N7—C81.349 (4)N17—C151.371 (4)
N7—C51.371 (4)N17—H17N0.83 (2)
N7—H7N0.83 (2)C11'—C191.490 (4)
C1'—C91.489 (4)C11'—C12'1.529 (4)
C1'—C2'1.536 (4)C11'—H11'1.0000
C1'—H1'1.0000C12'—C13'1.528 (4)
C2'—C3'1.513 (4)C12'—H12'1.0000
C2'—H2'1.0000C13'—C14'1.542 (4)
C3'—C4'1.527 (5)C13'—H13'1.0000
C3'—H3'1.0000C14'—C15'1.525 (4)
C4'—C5'1.525 (4)C14'—H14'1.0000
C4'—H4'1.0000C15'—H15A0.9900
C5'—H5A'0.9900C15'—H15B0.9900
C5'—H5B'0.9900C16'—H16A0.9800
C6'—H6A'0.9800C16'—H16B0.9800
C6'—H6B'0.9800C16'—H16C0.9800
C6'—H6C'0.9800C12—H120.9500
C2—H20.9500C14—C151.383 (4)
C4—C51.390 (4)C14—C191.411 (4)
C4—C91.406 (4)C15—C161.412 (4)
C5—C61.398 (4)C18—C191.382 (4)
C8—C91.389 (4)C18—H180.9500
C8—H80.9500O1W—H1WA0.96 (4)
S2—C16'1.791 (3)O1W—H2WA0.80 (4)
C6'—S1—C5'100.90 (16)C12'—O12'—H12O109.5
C2'—O2'—H2O'109.5C13'—O13'—H13O109.5
C3'—O3'—H3O'109.5C11'—N11'—C14'107.6 (2)
C1'—N1'—C4'107.7 (2)C11'—N11'—H11A111 (2)
C1'—N1'—H1N'106 (2)C14'—N11'—H11A108.9 (19)
C4'—N1'—H1N'110.5 (19)C11'—N11'—H11B112 (2)
C1'—N1'—H2N'106 (2)C14'—N11'—H11B112.3 (19)
C4'—N1'—H2N'112 (2)H11A—N11'—H11B105 (3)
H1N'—N1'—H2N'113 (3)C12—N11—C16119.1 (2)
C2—N1—C6119.0 (3)C12—N13—C14118.9 (3)
C2—N3—C4118.3 (3)C12—N13—H13N121 (2)
C2—N3—H3N119 (2)C14—N13—H13N119 (2)
C4—N3—H3N123 (2)C16—N16—H61A121 (2)
C6—N6—H6A122 (2)C16—N16—H61B119 (2)
C6—N6—H6B117 (2)H61A—N16—H61B119 (3)
H6A—N6—H6B117 (3)C18—N17—C15108.6 (2)
C8—N7—C5108.9 (2)C18—N17—H17N126 (2)
C8—N7—H7N134 (2)C15—N17—H17N126 (2)
C5—N7—H7N117 (2)C19—C11'—N11'112.0 (3)
C9—C1'—N1'111.8 (3)C19—C11'—C12'117.5 (2)
C9—C1'—C2'117.4 (3)N11'—C11'—C12'99.8 (2)
N1'—C1'—C2'100.8 (2)C19—C11'—H11'109.0
C9—C1'—H1'108.8N11'—C11'—H11'109.0
N1'—C1'—H1'108.8C12'—C11'—H11'109.0
C2'—C1'—H1'108.8O12'—C12'—C13'110.1 (2)
O2'—C2'—C3'111.5 (3)O12'—C12'—C11'115.6 (2)
O2'—C2'—C1'112.6 (2)C13'—C12'—C11'102.7 (2)
C3'—C2'—C1'102.3 (2)O12'—C12'—H12'109.4
O2'—C2'—H2'110.1C13'—C12'—H12'109.4
C3'—C2'—H2'110.1C11'—C12'—H12'109.4
C1'—C2'—H2'110.1O13'—C13'—C12'111.7 (3)
O3'—C3'—C2'110.8 (2)O13'—C13'—C14'106.9 (2)
O3'—C3'—C4'106.4 (2)C12'—C13'—C14'103.8 (2)
C2'—C3'—C4'104.5 (3)O13'—C13'—H13'111.4
O3'—C3'—H3'111.6C12'—C13'—H13'111.4
C2'—C3'—H3'111.6C14'—C13'—H13'111.4
C4'—C3'—H3'111.6C15'—C14'—N11'108.5 (2)
C5'—C4'—C3'114.8 (2)C15'—C14'—C13'115.3 (2)
C5'—C4'—N1'109.4 (2)N11'—C14'—C13'104.5 (2)
C3'—C4'—N1'104.0 (2)C15'—C14'—H14'109.5
C5'—C4'—H4'109.5N11'—C14'—H14'109.5
C3'—C4'—H4'109.5C13'—C14'—H14'109.5
N1'—C4'—H4'109.5C14'—C15'—S2113.4 (2)
C4'—C5'—S1111.8 (2)C14'—C15'—H15A108.9
C4'—C5'—H5A'109.3S2—C15'—H15A108.9
S1—C5'—H5A'109.3C14'—C15'—H15B108.9
C4'—C5'—H5B'109.3S2—C15'—H15B108.9
S1—C5'—H5B'109.3H15A—C15'—H15B107.7
H5A'—C5'—H5B'107.9S2—C16'—H16A109.5
S1—C6'—H6A'109.5S2—C16'—H16B109.5
S1—C6'—H6B'109.5H16A—C16'—H16B109.5
H6A'—C6'—H6B'109.5S2—C16'—H16C109.5
S1—C6'—H6C'109.5H16A—C16'—H16C109.5
H6A'—C6'—H6C'109.5H16B—C16'—H16C109.5
H6B'—C6'—H6C'109.5N11—C12—N13125.0 (3)
N1—C2—N3125.4 (3)N11—C12—H12117.5
N1—C2—H2117.3N13—C12—H12117.5
N3—C2—H2117.3N13—C14—C15118.0 (3)
N3—C4—C5118.5 (3)N13—C14—C19132.9 (3)
N3—C4—C9132.2 (3)C15—C14—C19109.1 (3)
C5—C4—C9109.2 (3)N17—C15—C14107.1 (2)
N7—C5—C4106.8 (2)N17—C15—C16131.9 (3)
N7—C5—C6132.5 (3)C14—C15—C16120.9 (3)
C4—C5—C6120.6 (3)N16—C16—N11118.5 (3)
N6—C6—N1118.2 (3)N16—C16—C15123.6 (3)
N6—C6—C5123.7 (3)N11—C16—C15117.9 (3)
N1—C6—C5118.1 (3)N17—C18—C19110.2 (2)
N7—C8—C9110.5 (3)N17—C18—H18124.9
N7—C8—H8124.7C19—C18—H18124.9
C9—C8—H8124.7C18—C19—C14104.8 (2)
C8—C9—C4104.5 (3)C18—C19—C11'127.8 (3)
C8—C9—C1'127.5 (3)C14—C19—C11'127.3 (2)
C4—C9—C1'128.0 (3)H1WA—O1W—H2WA109 (3)
C16'—S2—C15'100.49 (15)
C4'—N1'—C1'—C9155.7 (2)C14'—N11'—C11'—C19160.9 (2)
C4'—N1'—C1'—C2'30.2 (3)C14'—N11'—C11'—C12'35.8 (3)
C9—C1'—C2'—O2'74.6 (3)C19—C11'—C12'—O12'72.8 (4)
N1'—C1'—C2'—O2'163.8 (2)N11'—C11'—C12'—O12'166.0 (2)
C9—C1'—C2'—C3'165.6 (3)C19—C11'—C12'—C13'167.3 (3)
N1'—C1'—C2'—C3'44.0 (3)N11'—C11'—C12'—C13'46.1 (3)
O2'—C2'—C3'—O3'48.5 (3)O12'—C12'—C13'—O13'48.7 (3)
C1'—C2'—C3'—O3'72.1 (3)C11'—C12'—C13'—O13'75.0 (3)
O2'—C2'—C3'—C4'162.7 (2)O12'—C12'—C13'—C14'163.5 (2)
C1'—C2'—C3'—C4'42.2 (3)C11'—C12'—C13'—C14'39.8 (3)
O3'—C3'—C4'—C5'146.1 (2)C11'—N11'—C14'—C15'135.4 (2)
C2'—C3'—C4'—C5'96.7 (3)C11'—N11'—C14'—C13'11.9 (3)
O3'—C3'—C4'—N1'94.4 (3)O13'—C13'—C14'—C15'140.0 (2)
C2'—C3'—C4'—N1'22.9 (3)C12'—C13'—C14'—C15'101.8 (3)
C1'—N1'—C4'—C5'128.2 (3)O13'—C13'—C14'—N11'101.1 (3)
C1'—N1'—C4'—C3'5.1 (3)C12'—C13'—C14'—N11'17.1 (3)
C3'—C4'—C5'—S168.5 (3)N11'—C14'—C15'—S2176.47 (19)
N1'—C4'—C5'—S1175.00 (19)C13'—C14'—C15'—S266.8 (3)
C6'—S1—C5'—C4'84.8 (3)C16'—S2—C15'—C14'61.1 (3)
C6—N1—C2—N31.8 (5)C16—N11—C12—N131.7 (5)
C4—N3—C2—N12.4 (5)C14—N13—C12—N111.4 (5)
C2—N3—C4—C52.8 (4)C12—N13—C14—C151.1 (4)
C2—N3—C4—C9177.9 (3)C12—N13—C14—C19179.0 (3)
C8—N7—C5—C41.5 (3)C18—N17—C15—C140.8 (3)
C8—N7—C5—C6178.0 (3)C18—N17—C15—C16176.5 (3)
N3—C4—C5—N7177.7 (3)N13—C14—C15—N17178.9 (3)
C9—C4—C5—N71.7 (3)C19—C14—C15—N171.0 (3)
N3—C4—C5—C60.7 (4)N13—C14—C15—C163.3 (4)
C9—C4—C5—C6178.7 (3)C19—C14—C15—C16176.8 (3)
C2—N1—C6—N6175.6 (3)C12—N11—C16—N16179.2 (3)
C2—N1—C6—C55.2 (4)C12—N11—C16—C150.6 (4)
N7—C5—C6—N60.0 (6)N17—C15—C16—N161.3 (6)
C4—C5—C6—N6176.1 (3)C14—C15—C16—N16178.4 (3)
N7—C5—C6—N1179.1 (3)N17—C15—C16—N11179.8 (3)
C4—C5—C6—N14.7 (5)C14—C15—C16—N113.1 (4)
C5—N7—C8—C90.7 (4)C15—N17—C18—C190.4 (4)
N7—C8—C9—C40.3 (4)N17—C18—C19—C140.2 (4)
N7—C8—C9—C1'178.5 (3)N17—C18—C19—C11'176.6 (3)
N3—C4—C9—C8178.1 (3)N13—C14—C19—C18179.2 (3)
C5—C4—C9—C81.2 (4)C15—C14—C19—C180.7 (3)
N3—C4—C9—C1'3.2 (6)N13—C14—C19—C11'4.0 (6)
C5—C4—C9—C1'177.5 (3)C15—C14—C19—C11'176.1 (3)
N1'—C1'—C9—C888.6 (4)N11'—C11'—C19—C1888.6 (4)
C2'—C1'—C9—C827.1 (5)C12'—C11'—C19—C1826.0 (5)
N1'—C1'—C9—C489.8 (4)N11'—C11'—C19—C1487.5 (4)
C2'—C1'—C9—C4154.4 (3)C12'—C11'—C19—C14157.9 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O2—H2O···Cl1i0.842.273.082 (2)163
O3—H3O···O1Wii0.841.932.724 (4)158
N1—H1N···Cl1iii0.89 (3)2.32 (3)3.199 (3)169 (3)
N3—H3N···Cl40.85 (3)2.31 (3)3.097 (3)154 (3)
N1—H2N···Cl30.84 (3)2.29 (3)3.120 (3)171 (3)
N6—H6A···Cl4i0.83 (3)2.62 (3)3.223 (3)131 (2)
N6—H6B···Cl2iii0.84 (3)2.38 (3)3.196 (3)165 (3)
N7—H7N···Cl2iii0.83 (3)2.42 (3)3.232 (3)170 (3)
O1W—H1WA···N1iv0.96 (3)1.87 (4)2.804 (4)162 (3)
O1W—H2WA···Cl30.80 (4)2.35 (4)3.143 (3)173 (3)
N11—H11A···Cl20.92 (3)2.35 (3)3.268 (3)171 (3)
N11—H11B···Cl30.89 (3)2.34 (3)3.146 (3)151 (3)
O12—H12O···Cl2ii0.842.343.145 (2)162
N13—H13N···Cl40.87 (3)2.48 (3)3.228 (3)145 (3)
O13—H13O···S2ii0.842.573.364 (2)157
N17—H17N···Cl10.84 (3)2.39 (3)3.197 (3)163 (3)
N16—H61A···Cl10.85 (3)2.51 (3)3.351 (3)171 (3)
N16—H61B···Cl3iv0.82 (3)2.62 (3)3.311 (3)143 (3)
C2—H2···O130.952.463.383 (4)164
Symmetry codes: (i) x+2, y+1/2, z+1/2; (ii) x+1, y, z; (iii) x+1, y+1/2, z+1/2; (iv) x+1, y1/2, z+1/2.

Experimental details

Crystal data
Chemical formula2C12H19N5O2S2+·4Cl·H2O
Mr754.58
Crystal system, space groupOrthorhombic, P212121
Temperature (K)100
a, b, c (Å)7.0080 (14), 18.717 (4), 24.825 (5)
V3)3256.3 (11)
Z4
Radiation typeSynchrotron, λ = 0.92014 Å
µ (mm1)1.05
Crystal size (mm)0.23 × 0.20 × 0.15
Data collection
DiffractometerADSC Quantum CCD Detector
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3864, 3864, 3821
Rint0.000
θmax (°)29.6
(sin θ/λ)max1)0.537
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.027, 0.066, 1.06
No. of reflections3864
No. of parameters454
No. of restraints12
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.40, 0.24
Absolute structureFlack (1983), ???? Friedel pairs
Absolute structure parameter0.03 (3)

Computer programs: DENZO (Otwinowski & Minor, 1997), DENZO and SCALEPACK (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), ORTEP-3 (Farrugia, 1997), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O2'—H2O'···Cl1i0.842.273.082 (2)163
O3'—H3O'···O1Wii0.841.932.724 (4)158
N1'—H1N'···Cl1iii0.89 (3)2.32 (3)3.199 (3)169 (3)
N3—H3N···Cl40.85 (3)2.31 (3)3.097 (3)154 (3)
N1'—H2N'···Cl30.84 (3)2.29 (3)3.120 (3)171 (3)
N6—H6A···Cl4i0.83 (3)2.62 (3)3.223 (3)131 (2)
N6—H6B···Cl2iii0.84 (3)2.38 (3)3.196 (3)165 (3)
N7—H7N···Cl2iii0.83 (3)2.42 (3)3.232 (3)170 (3)
O1W—H1WA···N1iv0.96 (3)1.87 (4)2.804 (4)162 (3)
O1W—H2WA···Cl30.80 (4)2.35 (4)3.143 (3)173 (3)
N11'—H11A···Cl20.92 (3)2.35 (3)3.268 (3)171 (3)
N11'—H11B···Cl30.89 (3)2.34 (3)3.146 (3)151 (3)
O12'—H12O···Cl2ii0.842.343.145 (2)162
N13—H13N···Cl40.87 (3)2.48 (3)3.228 (3)145 (3)
O13'—H13O···S2ii0.842.573.364 (2)157
N17—H17N···Cl10.84 (3)2.39 (3)3.197 (3)163 (3)
N16—H61A···Cl10.85 (3)2.51 (3)3.351 (3)171 (3)
N16—H61B···Cl3iv0.82 (3)2.62 (3)3.311 (3)143 (3)
C2—H2···O13'0.952.463.383 (4)164
Symmetry codes: (i) x+2, y+1/2, z+1/2; (ii) x+1, y, z; (iii) x+1, y+1/2, z+1/2; (iv) x+1, y1/2, z+1/2.
Comparison of parameters between the two molecules in (I), ligand A in 1K27 and docked models (see Comment) top
ParameteraMolecule 1Molecule 2Ligand A in 1K27bNeMo1cDiMo1d
N1'—C1'—C9—C888.6 (4)88.7 (4)-54-56.2-61.1
C2'—C1'—C9—C4154.4 (3)157.9 (3)11-0.1-7.1
N1'—C1'—C2'—C3'44.0 (3)46.1 (3)-0.41.81.8
C1'—C2'—C3'—C4'-42.2 (3)-39.8 (3)-13-15.7-15.7
N1'—C4'—C5'—S1175.0 (2)176.5 (2)5053.7173.7
C3'—C4'—C5'—S1-68.5 (3)-66.8 (3)170170.1-69.9
C4'—C5'—S1—C6'-84.8 (3)-61.1 (3)7661.4172.5
Pyrrole RingeEnv.(C2')Twist C11'—C12'Env.(C4')Env.(C4')Env.(C4')
Envelope Δf (Å)0.663 (3)na0.340.370.37
Q(2) (Å)0.442 (3)0.453 (3)0.220.230.23
ϕ(2) (°)66.1 (4)58.0 (4)144136136
Relative energyg-256-2506200
Notes: (a) angles in °; (b) Ligand A, as the generated dication (see Comment); (c) NeMo1: docked neutral molecule 1 (without the N3 and one N1' H atoms); (d) DiMo1: docked from molecule 1 start, in dication form; (e) Env.(Cn) = Envelope with flap atom Cn; (f) Δ from four-atom envelope plane; (g) relative energy in kJ mol-1 for DFT-optimized coordinates from starting models above (see Comment).
 

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