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The first example of mol­ecular docking of the SARS-CoV-2 main protease for COVID-19 [Mpro, Protein Data Bank (PDB) code 7BQY] by a chalcone-based ligand, namely, (E)-1-(2,4-di­chloro­phen­yl)-3-[4-(morpholin-4-yl)phen­yl]prop-2-en-1-one, C19H17Cl2NO2, I, is presented. Two-dimensional (2D) LIGPLOT representations calculated for the inhibitor N3, viz. N-{[(5-methyl­isoxazol-3-yl)carbon­yl]alanyl}-L-valyl-N1-((1R,2Z)-4-(benz­yloxy)-4-oxo-1-{[(3R)-2-oxopyrrol­idin-3-yl]meth­yl}but-2-en­yl)-L-leucinamide, and 7BQY are included for com­parison with our chalcone-based complexes. The binding affinity of our chalcone ligand with 7BQY is −7.0 kcal mol−1, a high value which was attributed to the presence of a hydrogen bond, together with many hydro­phobic inter­actions between the drug and the active amino acid residues of the receptor. Docking studies were also performed, employing rigid and flexible binding modes for the ligand. The superposition of N3 and the chalcone docked into the binding pocket of 7BQY is also presented. The synthesis, single-crystal structure, Hirshfeld surface analysis (HSA) and spectral characterization of heterocyclic chalcone-based compound I, are also presented. The mol­ecules are stacked, with normal π–π inter­actions, in the crystal.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229620014217/ky3199sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229620014217/ky3199Isup2.hkl
Contains datablock I

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229620014217/ky3199Isup3.cml
Supplementary material

CCDC reference: 2011624

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2019); cell refinement: CrysAlis PRO (Rigaku OD, 2019); data reduction: CrysAlis PRO (Rigaku OD, 2019); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: SHELXL2018 (Sheldrick, 2015b) and WinGX (Farrugia, 2012).

(E)-1-(2,4-Dichlorophenyl)- 3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one top
Crystal data top
C19H17Cl2NO2F(000) = 376
Mr = 362.23Dx = 1.462 Mg m3
Monoclinic, P21Cu Kα radiation, λ = 1.54184 Å
a = 3.96521 (9) ÅCell parameters from 17383 reflections
b = 16.7005 (4) Åθ = 2.6–77.8°
c = 12.4252 (2) ŵ = 3.64 mm1
β = 91.185 (2)°T = 100 K
V = 822.63 (3) Å3Prism, yellow
Z = 20.15 × 0.13 × 0.12 mm
Data collection top
Rigaku XtaLAB Synergy Dualflex HyPix
diffractometer
3089 independent reflections
Radiation source: micro-focus sealed X-ray tube, PhotonJet (Cu) X-ray Source3079 reflections with I > 2σ(I)
Mirror monochromatorRint = 0.028
Detector resolution: 10.0000 pixels mm-1θmax = 72.4°, θmin = 3.6°
ω scansh = 44
Absorption correction: multi-scan
(CrysAlis PRO; Rigaku OD, 2019)
k = 1720
Tmin = 0.790, Tmax = 1.000l = 1515
17673 measured reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.024 w = 1/[σ2(Fo2) + (0.0463P)2 + 0.1638P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.064(Δ/σ)max < 0.001
S = 1.07Δρmax = 0.18 e Å3
3089 reflectionsΔρmin = 0.20 e Å3
217 parametersAbsolute structure: Flack x determined using 1385 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
1 restraintAbsolute structure parameter: 0.002 (9)
Primary atom site location: dual
Special details top

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

Refinement. The crystal used for analysis was a yellow cube cut down from a needle prism to ca 0.12 × 0.13 × 0.15 mm. This was mounted in oil on a small loop and fixed in the cold nitrogen stream on a Rigaku Oxford Diffraction XtaLAB Synergy diffractometer, equipped with Cu Kα radiation, HyPix detector and mirror monochromator. Intensity data were measured by thin-slice ω-scans. Total no. of reflections recorded, to θmax = 72.5°, was 17673 of which 3089 were unique (Rint = 0.028); 3079 were 'observed' with I > 2σI. Data were processed using the CrysAlisPro CCD and RED (Rigaku Oxford Diffraction Ltd., 2018) programs. The structure was determined by the intrinsic phasing routines in the SHELXT program (Sheldrick, 2015a) and refined by full-matrix least-squares methods, on F2's, in SHELXL (Sheldrick, 2015b). The non-hydrogen atoms were refined with anisotropic thermal parameters.

Scattering factors for neutral atoms were taken from International Tables (1992). Computer programs used in this analysis have been noted above, and were run through WinGX (Farrugia, 2012) on a Dell Optiplex 780 PC at the University of East Anglia.

The crystallographic data were deposited at the Cambridge Crystallographic Data Centre (CCDC) under a CCDC number:2011624. Copies of the data can be obtained, via www. ccdc.cam.ac.uk.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.9545 (5)0.73931 (13)0.27433 (17)0.0152 (4)
C21.0426 (5)0.73678 (13)0.38359 (17)0.0149 (4)
Cl21.22361 (12)0.65138 (3)0.44086 (4)0.01875 (13)
C31.0024 (6)0.80261 (15)0.45034 (16)0.0163 (4)
H31.0677360.8004000.5225970.020*
C40.8631 (5)0.87136 (14)0.40690 (17)0.0162 (4)
Cl40.81245 (14)0.95350 (3)0.49102 (4)0.02188 (14)
C50.7663 (6)0.87689 (14)0.29907 (18)0.0189 (4)
H50.6700260.9235280.2714250.023*
C60.8174 (6)0.81078 (14)0.23391 (17)0.0186 (4)
H60.7589460.8139970.1611630.022*
C71.0117 (5)0.67207 (13)0.19629 (16)0.0156 (4)
O71.1582 (4)0.68791 (10)0.11275 (13)0.0218 (3)
C80.8765 (6)0.59292 (15)0.22078 (18)0.0165 (4)
H80.7585010.5852030.2838610.020*
C90.9208 (5)0.53076 (14)0.15283 (17)0.0150 (4)
H91.0475090.5409900.0921920.018*
C110.7933 (5)0.45028 (14)0.16393 (16)0.0151 (4)
C120.8317 (5)0.39453 (14)0.08094 (17)0.0160 (4)
H120.9380620.4104800.0184660.019*
C130.7172 (5)0.31664 (14)0.08860 (17)0.0155 (4)
H130.7405960.2819110.0307250.019*
C140.5650 (5)0.28933 (13)0.18344 (16)0.0132 (4)
C150.5209 (5)0.34556 (14)0.26673 (16)0.0159 (4)
H150.4155070.3298140.3294610.019*
C160.6316 (5)0.42367 (14)0.25670 (17)0.0156 (4)
H160.5980260.4594440.3128360.019*
N170.4798 (4)0.20947 (12)0.19637 (14)0.0145 (4)
C180.3753 (5)0.16042 (14)0.10351 (16)0.0165 (4)
H18A0.5003150.1764680.0408010.020*
H18B0.1370910.1686340.0878780.020*
C190.4400 (6)0.07279 (14)0.12729 (18)0.0187 (4)
H19A0.3632740.0408350.0663660.022*
H19B0.6806420.0641730.1370770.022*
O200.2701 (4)0.04708 (10)0.22196 (13)0.0193 (3)
C210.3857 (5)0.09365 (14)0.31143 (17)0.0177 (4)
H21A0.6252380.0844220.3228960.021*
H21B0.2709850.0760530.3754540.021*
C220.3253 (5)0.18248 (14)0.29586 (17)0.0161 (4)
H22A0.0847980.1930570.2925220.019*
H22B0.4214970.2117820.3565110.019*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0183 (10)0.0116 (11)0.0158 (10)0.0028 (8)0.0015 (8)0.0019 (8)
C20.0167 (10)0.0114 (11)0.0166 (10)0.0002 (8)0.0023 (8)0.0020 (8)
Cl20.0279 (3)0.0127 (3)0.0157 (2)0.00367 (18)0.00087 (17)0.00193 (18)
C30.0182 (10)0.0162 (11)0.0144 (9)0.0017 (8)0.0025 (7)0.0003 (8)
C40.0198 (10)0.0089 (10)0.0201 (10)0.0020 (8)0.0054 (8)0.0019 (8)
Cl40.0339 (3)0.0124 (3)0.0196 (2)0.0030 (2)0.00575 (19)0.00228 (19)
C50.0226 (11)0.0131 (11)0.0210 (11)0.0018 (8)0.0007 (8)0.0033 (8)
C60.0267 (11)0.0139 (11)0.0151 (9)0.0008 (8)0.0014 (8)0.0018 (8)
C70.0190 (10)0.0139 (12)0.0139 (9)0.0001 (8)0.0000 (8)0.0019 (8)
O70.0327 (8)0.0164 (9)0.0164 (7)0.0016 (6)0.0067 (6)0.0020 (6)
C80.0193 (10)0.0149 (11)0.0154 (10)0.0013 (8)0.0027 (7)0.0009 (8)
C90.0160 (10)0.0155 (12)0.0135 (9)0.0009 (8)0.0007 (7)0.0023 (8)
C110.0160 (9)0.0145 (11)0.0148 (9)0.0029 (8)0.0003 (7)0.0002 (8)
C120.0187 (10)0.0150 (11)0.0144 (9)0.0014 (8)0.0029 (8)0.0012 (8)
C130.0190 (10)0.0133 (11)0.0143 (9)0.0021 (8)0.0011 (7)0.0010 (8)
C140.0130 (9)0.0118 (11)0.0146 (9)0.0012 (7)0.0013 (7)0.0002 (8)
C150.0183 (10)0.0167 (11)0.0127 (9)0.0008 (8)0.0023 (7)0.0008 (8)
C160.0194 (10)0.0134 (11)0.0142 (9)0.0001 (8)0.0016 (8)0.0019 (8)
N170.0176 (8)0.0120 (10)0.0139 (8)0.0009 (7)0.0014 (6)0.0008 (7)
C180.0186 (9)0.0152 (12)0.0156 (9)0.0017 (8)0.0004 (7)0.0004 (9)
C190.0191 (10)0.0155 (12)0.0214 (11)0.0017 (8)0.0003 (8)0.0016 (9)
O200.0201 (8)0.0150 (9)0.0227 (8)0.0043 (6)0.0010 (6)0.0017 (6)
C210.0168 (10)0.0158 (11)0.0204 (10)0.0016 (8)0.0011 (8)0.0031 (8)
C220.0170 (10)0.0165 (12)0.0148 (9)0.0018 (8)0.0005 (7)0.0019 (8)
Geometric parameters (Å, º) top
C1—C21.396 (3)C13—C141.411 (3)
C1—C61.400 (3)C13—H130.9300
C1—C71.504 (3)C14—N171.386 (3)
C2—C31.388 (3)C14—C151.411 (3)
C2—Cl21.742 (2)C15—C161.383 (3)
C3—C41.379 (3)C15—H150.9300
C3—H30.9300C16—H160.9300
C4—C51.389 (3)N17—C221.462 (3)
C4—Cl41.739 (2)N17—C181.468 (3)
C5—C61.387 (3)C18—C191.514 (3)
C5—H50.9300C18—H18A0.9700
C6—H60.9300C18—H18B0.9700
C7—O71.229 (3)C19—O201.433 (3)
C7—C81.461 (3)C19—H19A0.9700
C8—C91.352 (3)C19—H19B0.9700
C8—H80.9300O20—C211.425 (3)
C9—C111.444 (3)C21—C221.514 (3)
C9—H90.9300C21—H21A0.9700
C11—C121.400 (3)C21—H21B0.9700
C11—C161.403 (3)C22—H22A0.9700
C12—C131.382 (3)C22—H22B0.9700
C12—H120.9300
C2—C1—C6117.5 (2)N17—C14—C15121.41 (19)
C2—C1—C7124.5 (2)C13—C14—C15117.3 (2)
C6—C1—C7117.90 (18)C16—C15—C14121.16 (19)
C3—C2—C1121.8 (2)C16—C15—H15119.4
C3—C2—Cl2117.12 (16)C14—C15—H15119.4
C1—C2—Cl2121.00 (17)C15—C16—C11121.6 (2)
C4—C3—C2118.39 (19)C15—C16—H16119.2
C4—C3—H3120.8C11—C16—H16119.2
C2—C3—H3120.8C14—N17—C22120.14 (18)
C3—C4—C5122.2 (2)C14—N17—C18120.77 (17)
C3—C4—Cl4118.15 (17)C22—N17—C18112.09 (17)
C5—C4—Cl4119.62 (18)N17—C18—C19110.01 (17)
C6—C5—C4118.0 (2)N17—C18—H18A109.7
C6—C5—H5121.0C19—C18—H18A109.7
C4—C5—H5121.0N17—C18—H18B109.7
C5—C6—C1122.0 (2)C19—C18—H18B109.7
C5—C6—H6119.0H18A—C18—H18B108.2
C1—C6—H6119.0O20—C19—C18111.65 (18)
O7—C7—C8123.6 (2)O20—C19—H19A109.3
O7—C7—C1117.66 (19)C18—C19—H19A109.3
C8—C7—C1118.71 (18)O20—C19—H19B109.3
C9—C8—C7120.8 (2)C18—C19—H19B109.3
C9—C8—H8119.6H19A—C19—H19B108.0
C7—C8—H8119.6C21—O20—C19109.14 (16)
C8—C9—C11127.2 (2)O20—C21—C22112.81 (17)
C8—C9—H9116.4O20—C21—H21A109.0
C11—C9—H9116.4C22—C21—H21A109.0
C12—C11—C16116.9 (2)O20—C21—H21B109.0
C12—C11—C9120.35 (19)C22—C21—H21B109.0
C16—C11—C9122.7 (2)H21A—C21—H21B107.8
C13—C12—C11122.3 (2)N17—C22—C21110.01 (18)
C13—C12—H12118.8N17—C22—H22A109.7
C11—C12—H12118.8C21—C22—H22A109.7
C12—C13—C14120.6 (2)N17—C22—H22B109.7
C12—C13—H13119.7C21—C22—H22B109.7
C14—C13—H13119.7H22A—C22—H22B108.2
N17—C14—C13121.16 (19)
C6—C1—C2—C31.0 (3)C16—C11—C12—C130.0 (3)
C7—C1—C2—C3176.0 (2)C9—C11—C12—C13179.2 (2)
C6—C1—C2—Cl2178.56 (17)C11—C12—C13—C142.2 (3)
C7—C1—C2—Cl21.6 (3)C12—C13—C14—N17173.46 (19)
C1—C2—C3—C41.7 (3)C12—C13—C14—C153.0 (3)
Cl2—C2—C3—C4179.31 (17)N17—C14—C15—C16174.66 (19)
C2—C3—C4—C50.7 (3)C13—C14—C15—C161.8 (3)
C2—C3—C4—Cl4179.84 (16)C14—C15—C16—C110.3 (3)
C3—C4—C5—C60.9 (3)C12—C11—C16—C151.2 (3)
Cl4—C4—C5—C6178.58 (17)C9—C11—C16—C15178.0 (2)
C4—C5—C6—C11.5 (3)C13—C14—N17—C22179.40 (18)
C2—C1—C6—C50.6 (3)C15—C14—N17—C223.0 (3)
C7—C1—C6—C5177.8 (2)C13—C14—N17—C1832.2 (3)
C2—C1—C7—O7128.3 (2)C15—C14—N17—C18151.44 (19)
C6—C1—C7—O748.7 (3)C14—N17—C18—C19155.90 (18)
C2—C1—C7—C854.8 (3)C22—N17—C18—C1953.4 (2)
C6—C1—C7—C8128.2 (2)N17—C18—C19—O2057.1 (2)
O7—C7—C8—C93.1 (4)C18—C19—O20—C2159.5 (2)
C1—C7—C8—C9179.78 (19)C19—O20—C21—C2258.9 (2)
C7—C8—C9—C11177.70 (19)C14—N17—C22—C21156.88 (18)
C8—C9—C11—C12173.4 (2)C18—N17—C22—C2152.2 (2)
C8—C9—C11—C167.4 (4)O20—C21—C22—N1755.5 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C13—H13···O7i0.932.423.343 (3)176
C18—H18A···O7i0.972.373.326 (3)168
Symmetry code: (i) x+2, y1/2, z.
Torsion angles (°) of the keto–ethene group in selected chalcone molecules plus torsion angles (°) of the keto–ethene group after ligand–protein interaction top
C16—C11—C9—C8C11—C9—C8—C7C9—C8—C7—O7C9—C8—C7—C1C8—C7—C1—C6Reference
-7.4 (4)-177.70 (19)3.1 (4)179.78 (19)-128.2 (2)This study
35.7-177..620.2-162.9-47.3This study*
11.0-176.816.3-163.0-157.5Treadwell (2006)
12.8178.57.0-173.0169.0Li & Su (1994)
2.5-169.511.8-179.8163.8Wu et al., (2014b)
-7.1179.9-8.5170.7166.8Barsky et al. (2008); compound 3
Note: (*) the torsion angles for the keto–ethene after the interaction with 7bqy.
Bond lengths (Å) in the keto–ethene group in related chalcones (Ravishankar et al., 2003) top
ADD SCHEME HERE
O7—C7C7—C8C8C9Reference
1.229 (3)1.461 (3)1.352 (3)This study
1.224 (2)1.474 (4)1.326 (3)Treadwell (2006)
1.227 (4)1.474 (4)1.313 (4)Li & Su (1994)
1.240 (2)1.459 (2)1.327 (3)Wu et al. (2014a,b)
1.226 (2)1.471 (2)1.325 (2)Tang (2009)
Analysis results for all nine poses of the chalcone-based ligand with 7bqy top
PosesBinding affinities (kcal mol-1)RMSD lower limitRMSD upper limitNo. of hydrogen bonds, residue, D (Å)
1-7.00.00.01, Arg 188(A), 2.89
2-7.01.5352.0453, Arg 188(A), 2.70; Gly 143(A), 3.08; Thr190(A), 3.10
3-6.94.2719.5381, His164(A), 2.7
4-6.81.2911.7221, Glu166(A), 2.68
5-6.74.4179.6521, Gly143(A), 3.05
6-6.75.00110.531, Glu166(A), 3.00
7-6.64.4149.5850
8-6.62.7593.7671, Thr190(A), 2.70
9-6.41.6522.1141, Glu166(A), 2.80
 

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