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The first example of molecular docking of the SARS-CoV-2 main protease for COVID-19 [M
pro, 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, C
19H
17Cl
2NO
2,
I, is presented. Two-dimensional (2D)
LIGPLOT representations calculated for the inhibitor
N3,
viz. N-{[(5-methylisoxazol-3-yl)carbonyl]alanyl}-
L-valyl-
N1-((1
R,2
Z)-4-(benzyloxy)-4-oxo-1-{[(3
R)-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
CCDC reference: 2011624
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
C19H17Cl2NO2 | F(000) = 376 |
Mr = 362.23 | Dx = 1.462 Mg m−3 |
Monoclinic, P21 | Cu Kα radiation, λ = 1.54184 Å |
a = 3.96521 (9) Å | Cell parameters from 17383 reflections |
b = 16.7005 (4) Å | θ = 2.6–77.8° |
c = 12.4252 (2) Å | µ = 3.64 mm−1 |
β = 91.185 (2)° | T = 100 K |
V = 822.63 (3) Å3 | Prism, yellow |
Z = 2 | 0.15 × 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 Source | 3079 reflections with I > 2σ(I) |
Mirror monochromator | Rint = 0.028 |
Detector resolution: 10.0000 pixels mm-1 | θmax = 72.4°, θmin = 3.6° |
ω scans | h = −4→4 |
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2019) | k = −17→20 |
Tmin = 0.790, Tmax = 1.000 | l = −15→15 |
17673 measured reflections | |
Refinement top
Refinement on F2 | Hydrogen site location: inferred from neighbouring sites |
Least-squares matrix: full | H-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 = 1.07 | Δρmax = 0.18 e Å−3 |
3089 reflections | Δρmin = −0.20 e Å−3 |
217 parameters | Absolute structure: Flack x determined using 1385 quotients [(I+)-(I-)]/[(I+)+(I-)]
(Parsons et al., 2013) |
1 restraint | Absolute 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 | x | y | z | Uiso*/Ueq | |
C1 | 0.9545 (5) | 0.73931 (13) | 0.27433 (17) | 0.0152 (4) | |
C2 | 1.0426 (5) | 0.73678 (13) | 0.38359 (17) | 0.0149 (4) | |
Cl2 | 1.22361 (12) | 0.65138 (3) | 0.44086 (4) | 0.01875 (13) | |
C3 | 1.0024 (6) | 0.80261 (15) | 0.45034 (16) | 0.0163 (4) | |
H3 | 1.067736 | 0.800400 | 0.522597 | 0.020* | |
C4 | 0.8631 (5) | 0.87136 (14) | 0.40690 (17) | 0.0162 (4) | |
Cl4 | 0.81245 (14) | 0.95350 (3) | 0.49102 (4) | 0.02188 (14) | |
C5 | 0.7663 (6) | 0.87689 (14) | 0.29907 (18) | 0.0189 (4) | |
H5 | 0.670026 | 0.923528 | 0.271425 | 0.023* | |
C6 | 0.8174 (6) | 0.81078 (14) | 0.23391 (17) | 0.0186 (4) | |
H6 | 0.758946 | 0.813997 | 0.161163 | 0.022* | |
C7 | 1.0117 (5) | 0.67207 (13) | 0.19629 (16) | 0.0156 (4) | |
O7 | 1.1582 (4) | 0.68791 (10) | 0.11275 (13) | 0.0218 (3) | |
C8 | 0.8765 (6) | 0.59292 (15) | 0.22078 (18) | 0.0165 (4) | |
H8 | 0.758501 | 0.585203 | 0.283861 | 0.020* | |
C9 | 0.9208 (5) | 0.53076 (14) | 0.15283 (17) | 0.0150 (4) | |
H9 | 1.047509 | 0.540990 | 0.092192 | 0.018* | |
C11 | 0.7933 (5) | 0.45028 (14) | 0.16393 (16) | 0.0151 (4) | |
C12 | 0.8317 (5) | 0.39453 (14) | 0.08094 (17) | 0.0160 (4) | |
H12 | 0.938062 | 0.410480 | 0.018466 | 0.019* | |
C13 | 0.7172 (5) | 0.31664 (14) | 0.08860 (17) | 0.0155 (4) | |
H13 | 0.740596 | 0.281911 | 0.030725 | 0.019* | |
C14 | 0.5650 (5) | 0.28933 (13) | 0.18344 (16) | 0.0132 (4) | |
C15 | 0.5209 (5) | 0.34556 (14) | 0.26673 (16) | 0.0159 (4) | |
H15 | 0.415507 | 0.329814 | 0.329461 | 0.019* | |
C16 | 0.6316 (5) | 0.42367 (14) | 0.25670 (17) | 0.0156 (4) | |
H16 | 0.598026 | 0.459444 | 0.312836 | 0.019* | |
N17 | 0.4798 (4) | 0.20947 (12) | 0.19637 (14) | 0.0145 (4) | |
C18 | 0.3753 (5) | 0.16042 (14) | 0.10351 (16) | 0.0165 (4) | |
H18A | 0.500315 | 0.176468 | 0.040801 | 0.020* | |
H18B | 0.137091 | 0.168634 | 0.087878 | 0.020* | |
C19 | 0.4400 (6) | 0.07279 (14) | 0.12729 (18) | 0.0187 (4) | |
H19A | 0.363274 | 0.040835 | 0.066366 | 0.022* | |
H19B | 0.680642 | 0.064173 | 0.137077 | 0.022* | |
O20 | 0.2701 (4) | 0.04708 (10) | 0.22196 (13) | 0.0193 (3) | |
C21 | 0.3857 (5) | 0.09365 (14) | 0.31143 (17) | 0.0177 (4) | |
H21A | 0.625238 | 0.084422 | 0.322896 | 0.021* | |
H21B | 0.270985 | 0.076053 | 0.375454 | 0.021* | |
C22 | 0.3253 (5) | 0.18248 (14) | 0.29586 (17) | 0.0161 (4) | |
H22A | 0.084798 | 0.193057 | 0.292522 | 0.019* | |
H22B | 0.421497 | 0.211782 | 0.356511 | 0.019* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.0183 (10) | 0.0116 (11) | 0.0158 (10) | −0.0028 (8) | 0.0015 (8) | 0.0019 (8) |
C2 | 0.0167 (10) | 0.0114 (11) | 0.0166 (10) | 0.0002 (8) | 0.0023 (8) | 0.0020 (8) |
Cl2 | 0.0279 (3) | 0.0127 (3) | 0.0157 (2) | 0.00367 (18) | −0.00087 (17) | 0.00193 (18) |
C3 | 0.0182 (10) | 0.0162 (11) | 0.0144 (9) | −0.0017 (8) | 0.0025 (7) | 0.0003 (8) |
C4 | 0.0198 (10) | 0.0089 (10) | 0.0201 (10) | −0.0020 (8) | 0.0054 (8) | −0.0019 (8) |
Cl4 | 0.0339 (3) | 0.0124 (3) | 0.0196 (2) | 0.0030 (2) | 0.00575 (19) | −0.00228 (19) |
C5 | 0.0226 (11) | 0.0131 (11) | 0.0210 (11) | 0.0018 (8) | 0.0007 (8) | 0.0033 (8) |
C6 | 0.0267 (11) | 0.0139 (11) | 0.0151 (9) | 0.0008 (8) | −0.0014 (8) | 0.0018 (8) |
C7 | 0.0190 (10) | 0.0139 (12) | 0.0139 (9) | 0.0001 (8) | 0.0000 (8) | 0.0019 (8) |
O7 | 0.0327 (8) | 0.0164 (9) | 0.0164 (7) | −0.0016 (6) | 0.0067 (6) | 0.0020 (6) |
C8 | 0.0193 (10) | 0.0149 (11) | 0.0154 (10) | −0.0013 (8) | 0.0027 (7) | 0.0009 (8) |
C9 | 0.0160 (10) | 0.0155 (12) | 0.0135 (9) | 0.0009 (8) | 0.0007 (7) | 0.0023 (8) |
C11 | 0.0160 (9) | 0.0145 (11) | 0.0148 (9) | 0.0029 (8) | 0.0003 (7) | 0.0002 (8) |
C12 | 0.0187 (10) | 0.0150 (11) | 0.0144 (9) | 0.0014 (8) | 0.0029 (8) | 0.0012 (8) |
C13 | 0.0190 (10) | 0.0133 (11) | 0.0143 (9) | 0.0021 (8) | 0.0011 (7) | −0.0010 (8) |
C14 | 0.0130 (9) | 0.0118 (11) | 0.0146 (9) | 0.0012 (7) | −0.0013 (7) | −0.0002 (8) |
C15 | 0.0183 (10) | 0.0167 (11) | 0.0127 (9) | 0.0008 (8) | 0.0023 (7) | −0.0008 (8) |
C16 | 0.0194 (10) | 0.0134 (11) | 0.0142 (9) | 0.0001 (8) | 0.0016 (8) | −0.0019 (8) |
N17 | 0.0176 (8) | 0.0120 (10) | 0.0139 (8) | −0.0009 (7) | 0.0014 (6) | −0.0008 (7) |
C18 | 0.0186 (9) | 0.0152 (12) | 0.0156 (9) | −0.0017 (8) | −0.0004 (7) | −0.0004 (9) |
C19 | 0.0191 (10) | 0.0155 (12) | 0.0214 (11) | −0.0017 (8) | −0.0003 (8) | −0.0016 (9) |
O20 | 0.0201 (8) | 0.0150 (9) | 0.0227 (8) | −0.0043 (6) | −0.0010 (6) | 0.0017 (6) |
C21 | 0.0168 (10) | 0.0158 (11) | 0.0204 (10) | −0.0016 (8) | −0.0011 (8) | 0.0031 (8) |
C22 | 0.0170 (10) | 0.0165 (12) | 0.0148 (9) | −0.0018 (8) | 0.0005 (7) | 0.0019 (8) |
Geometric parameters (Å, º) top
C1—C2 | 1.396 (3) | C13—C14 | 1.411 (3) |
C1—C6 | 1.400 (3) | C13—H13 | 0.9300 |
C1—C7 | 1.504 (3) | C14—N17 | 1.386 (3) |
C2—C3 | 1.388 (3) | C14—C15 | 1.411 (3) |
C2—Cl2 | 1.742 (2) | C15—C16 | 1.383 (3) |
C3—C4 | 1.379 (3) | C15—H15 | 0.9300 |
C3—H3 | 0.9300 | C16—H16 | 0.9300 |
C4—C5 | 1.389 (3) | N17—C22 | 1.462 (3) |
C4—Cl4 | 1.739 (2) | N17—C18 | 1.468 (3) |
C5—C6 | 1.387 (3) | C18—C19 | 1.514 (3) |
C5—H5 | 0.9300 | C18—H18A | 0.9700 |
C6—H6 | 0.9300 | C18—H18B | 0.9700 |
C7—O7 | 1.229 (3) | C19—O20 | 1.433 (3) |
C7—C8 | 1.461 (3) | C19—H19A | 0.9700 |
C8—C9 | 1.352 (3) | C19—H19B | 0.9700 |
C8—H8 | 0.9300 | O20—C21 | 1.425 (3) |
C9—C11 | 1.444 (3) | C21—C22 | 1.514 (3) |
C9—H9 | 0.9300 | C21—H21A | 0.9700 |
C11—C12 | 1.400 (3) | C21—H21B | 0.9700 |
C11—C16 | 1.403 (3) | C22—H22A | 0.9700 |
C12—C13 | 1.382 (3) | C22—H22B | 0.9700 |
C12—H12 | 0.9300 | | |
| | | |
C2—C1—C6 | 117.5 (2) | N17—C14—C15 | 121.41 (19) |
C2—C1—C7 | 124.5 (2) | C13—C14—C15 | 117.3 (2) |
C6—C1—C7 | 117.90 (18) | C16—C15—C14 | 121.16 (19) |
C3—C2—C1 | 121.8 (2) | C16—C15—H15 | 119.4 |
C3—C2—Cl2 | 117.12 (16) | C14—C15—H15 | 119.4 |
C1—C2—Cl2 | 121.00 (17) | C15—C16—C11 | 121.6 (2) |
C4—C3—C2 | 118.39 (19) | C15—C16—H16 | 119.2 |
C4—C3—H3 | 120.8 | C11—C16—H16 | 119.2 |
C2—C3—H3 | 120.8 | C14—N17—C22 | 120.14 (18) |
C3—C4—C5 | 122.2 (2) | C14—N17—C18 | 120.77 (17) |
C3—C4—Cl4 | 118.15 (17) | C22—N17—C18 | 112.09 (17) |
C5—C4—Cl4 | 119.62 (18) | N17—C18—C19 | 110.01 (17) |
C6—C5—C4 | 118.0 (2) | N17—C18—H18A | 109.7 |
C6—C5—H5 | 121.0 | C19—C18—H18A | 109.7 |
C4—C5—H5 | 121.0 | N17—C18—H18B | 109.7 |
C5—C6—C1 | 122.0 (2) | C19—C18—H18B | 109.7 |
C5—C6—H6 | 119.0 | H18A—C18—H18B | 108.2 |
C1—C6—H6 | 119.0 | O20—C19—C18 | 111.65 (18) |
O7—C7—C8 | 123.6 (2) | O20—C19—H19A | 109.3 |
O7—C7—C1 | 117.66 (19) | C18—C19—H19A | 109.3 |
C8—C7—C1 | 118.71 (18) | O20—C19—H19B | 109.3 |
C9—C8—C7 | 120.8 (2) | C18—C19—H19B | 109.3 |
C9—C8—H8 | 119.6 | H19A—C19—H19B | 108.0 |
C7—C8—H8 | 119.6 | C21—O20—C19 | 109.14 (16) |
C8—C9—C11 | 127.2 (2) | O20—C21—C22 | 112.81 (17) |
C8—C9—H9 | 116.4 | O20—C21—H21A | 109.0 |
C11—C9—H9 | 116.4 | C22—C21—H21A | 109.0 |
C12—C11—C16 | 116.9 (2) | O20—C21—H21B | 109.0 |
C12—C11—C9 | 120.35 (19) | C22—C21—H21B | 109.0 |
C16—C11—C9 | 122.7 (2) | H21A—C21—H21B | 107.8 |
C13—C12—C11 | 122.3 (2) | N17—C22—C21 | 110.01 (18) |
C13—C12—H12 | 118.8 | N17—C22—H22A | 109.7 |
C11—C12—H12 | 118.8 | C21—C22—H22A | 109.7 |
C12—C13—C14 | 120.6 (2) | N17—C22—H22B | 109.7 |
C12—C13—H13 | 119.7 | C21—C22—H22B | 109.7 |
C14—C13—H13 | 119.7 | H22A—C22—H22B | 108.2 |
N17—C14—C13 | 121.16 (19) | | |
| | | |
C6—C1—C2—C3 | −1.0 (3) | C16—C11—C12—C13 | 0.0 (3) |
C7—C1—C2—C3 | 176.0 (2) | C9—C11—C12—C13 | 179.2 (2) |
C6—C1—C2—Cl2 | −178.56 (17) | C11—C12—C13—C14 | −2.2 (3) |
C7—C1—C2—Cl2 | −1.6 (3) | C12—C13—C14—N17 | −173.46 (19) |
C1—C2—C3—C4 | 1.7 (3) | C12—C13—C14—C15 | 3.0 (3) |
Cl2—C2—C3—C4 | 179.31 (17) | N17—C14—C15—C16 | 174.66 (19) |
C2—C3—C4—C5 | −0.7 (3) | C13—C14—C15—C16 | −1.8 (3) |
C2—C3—C4—Cl4 | 179.84 (16) | C14—C15—C16—C11 | −0.3 (3) |
C3—C4—C5—C6 | −0.9 (3) | C12—C11—C16—C15 | 1.2 (3) |
Cl4—C4—C5—C6 | 178.58 (17) | C9—C11—C16—C15 | −178.0 (2) |
C4—C5—C6—C1 | 1.5 (3) | C13—C14—N17—C22 | 179.40 (18) |
C2—C1—C6—C5 | −0.6 (3) | C15—C14—N17—C22 | 3.0 (3) |
C7—C1—C6—C5 | −177.8 (2) | C13—C14—N17—C18 | −32.2 (3) |
C2—C1—C7—O7 | −128.3 (2) | C15—C14—N17—C18 | 151.44 (19) |
C6—C1—C7—O7 | 48.7 (3) | C14—N17—C18—C19 | 155.90 (18) |
C2—C1—C7—C8 | 54.8 (3) | C22—N17—C18—C19 | −53.4 (2) |
C6—C1—C7—C8 | −128.2 (2) | N17—C18—C19—O20 | 57.1 (2) |
O7—C7—C8—C9 | 3.1 (4) | C18—C19—O20—C21 | −59.5 (2) |
C1—C7—C8—C9 | 179.78 (19) | C19—O20—C21—C22 | 58.9 (2) |
C7—C8—C9—C11 | −177.70 (19) | C14—N17—C22—C21 | −156.88 (18) |
C8—C9—C11—C12 | 173.4 (2) | C18—N17—C22—C21 | 52.2 (2) |
C8—C9—C11—C16 | −7.4 (4) | O20—C21—C22—N17 | −55.5 (2) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
C13—H13···O7i | 0.93 | 2.42 | 3.343 (3) | 176 |
C18—H18A···O7i | 0.97 | 2.37 | 3.326 (3) | 168 |
Symmetry code: (i) −x+2, y−1/2, −z. |
Torsion angles (°) of the keto–ethene group in selected chalcone molecules
plus torsion angles (°) of the keto–ethene group after ligand–protein
interaction topC16—C11—C9—C8 | C11—C9—C8—C7 | C9—C8—C7—O7 | C9—C8—C7—C1 | C8—C7—C1—C6 | Reference |
-7.4 (4) | -177.70 (19) | 3.1 (4) | 179.78 (19) | -128.2 (2) | This study |
35.7 | -177..6 | 20.2 | -162.9 | -47.3 | This study* |
11.0 | -176.8 | 16.3 | -163.0 | -157.5 | Treadwell (2006) |
12.8 | 178.5 | 7.0 | -173.0 | 169.0 | Li & Su (1994) |
2.5 | -169.5 | 11.8 | -179.8 | 163.8 | Wu et al., (2014b) |
-7.1 | 179.9 | -8.5 | 170.7 | 166.8 | Barsky 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) topO7—C7 | C7—C8 | C8═C9 | Reference |
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 topPoses | Binding affinities (kcal mol-1) | RMSD lower limit | RMSD upper limit | No. of hydrogen bonds, residue, D (Å) |
1 | -7.0 | 0.0 | 0.0 | 1, Arg 188(A), 2.89 |
2 | -7.0 | 1.535 | 2.045 | 3, Arg 188(A), 2.70; Gly 143(A), 3.08; Thr190(A), 3.10 |
3 | -6.9 | 4.271 | 9.538 | 1, His164(A), 2.7 |
4 | -6.8 | 1.291 | 1.722 | 1, Glu166(A), 2.68 |
5 | -6.7 | 4.417 | 9.652 | 1, Gly143(A), 3.05 |
6 | -6.7 | 5.001 | 10.53 | 1, Glu166(A), 3.00 |
7 | -6.6 | 4.414 | 9.585 | 0 |
8 | -6.6 | 2.759 | 3.767 | 1, Thr190(A), 2.70 |
9 | -6.4 | 1.652 | 2.114 | 1, Glu166(A), 2.80 |
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