Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides
Kocek, Hugo; Chalupská, Dominika; Dejmek, Milan; Dvořáková, Alexandra; Zgarbová, Michala; Šála, Michal; Chalupský, Karel; Krafčíková, Petra; Otava, Tomáš; Drexler, Matus; Procházková, Eliška; Klepetářová, Blanka; Štefek, Milan; Kozic, Ján; Mertlíková-Kaiserová, Helena; Boura, Evzen; Weber, Jan; Nencka, Radim; RSC Medicinal Chemistry  (2024) –; doi:10.1039/D4MD00422A

data_7249173
_publ_section_title
;
 Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors
 based on adenosine 5&#x2032;-carboxamides
;
_journal_name_full               'RSC Medicinal Chemistry'
_journal_paper_doi               10.1039/D4MD00422A
_journal_year                    2024
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C39 H50 N8 O5 Si2, C2 H3 N'
_chemical_formula_sum            'C41 H53 N9 O5 Si2'
_chemical_formula_weight         808.10
_chemical_name_systematic
(2S,3R,4R,5R)-5-(4-amino-5-(pyrimidin-5-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-N-(4-methyl-2-oxo-1,2-dihydroquinolin-7-yl)tetrahydrofuran-2-carboxamide
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   difmap
_atom_sites_solution_primary     direct
_audit_update_record
;
2024-06-05 deposited with the CCDC.	2024-07-26 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 99.3520(9)
_cell_angle_gamma                90
_cell_formula_units_Z            2
_cell_length_a                   13.5790(4)
_cell_length_b                   11.3344(3)
_cell_length_c                   14.3892(4)
_cell_measurement_reflns_used    9948
_cell_measurement_temperature    293
_cell_measurement_theta_max      72.1644
_cell_measurement_theta_min      3.2985
_cell_volume                     2185.20(11)
_computing_cell_refinement       'Apex3 (Bruker AXS, 2015)'
_computing_data_collection       'Apex3 (Bruker AXS, 2015)'
_computing_data_reduction        'Apex3 (Bruker AXS, 2015)'
_computing_molecular_graphics    'CAMERON (Watkin et al., 1996)'
_computing_publication_material  'CRYSTALS (Betteridge et al., 2003)'
_computing_structure_refinement  'CRYSTALS (Betteridge et al., 2003)'
_computing_structure_solution    'SIR92 (Altomare et al., 1994)'
_diffrn_ambient_temperature      293
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 1.000
_diffrn_measurement_device       Area
_diffrn_measurement_device_type  'Bruker Kappa Apex2'
_diffrn_measurement_method       '\f & \w scans'
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.028
_diffrn_reflns_av_unetI/netI     0.046
_diffrn_reflns_limit_h_max       16
_diffrn_reflns_limit_h_min       -16
_diffrn_reflns_limit_k_max       13
_diffrn_reflns_limit_k_min       -14
_diffrn_reflns_limit_l_max       17
_diffrn_reflns_limit_l_min       -17
_diffrn_reflns_number            49727
_diffrn_reflns_theta_full        72.211
_diffrn_reflns_theta_max         72.211
_diffrn_reflns_theta_min         3.112
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    1.166
_exptl_absorpt_correction_T_max  1.00
_exptl_absorpt_correction_T_min  0.85
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details   'SADABS (Siemens, 1996)'
_exptl_crystal_colour            colorless
_exptl_crystal_density_diffrn    1.228
_exptl_crystal_density_meas      ?
_exptl_crystal_density_method    'not measured'
_exptl_crystal_description       plate
_exptl_crystal_F_000             860
_exptl_crystal_size_max          0.294
_exptl_crystal_size_mid          0.116
_exptl_crystal_size_min          0.062
_refine_diff_density_max         0.06
_refine_diff_density_min         -0.04
_refine_ls_abs_structure_details
; 
 Parsons, Flack & Wagner (2013), 
 3455 Friedel Pairs 
;
_refine_ls_abs_structure_Flack   0.035(4)
_refine_ls_extinction_coef       60(4)
_refine_ls_extinction_method     'Larson (1970), Equation 22'
_refine_ls_goodness_of_fit_ref   0.9960
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     516
_refine_ls_number_reflns         8393
_refine_ls_number_restraints     1
_refine_ls_R_factor_all          0.0255
_refine_ls_R_factor_gt           0.0249
_refine_ls_shift/su_max          0.0004770
_refine_ls_shift/su_mean         0.0000287
_refine_ls_structure_factor_coef F
_refine_ls_weighting_details
;
 Method = Chebychev polynomial, (Carruthers & Watkin, 1979) 
 W = 1.0/[A[0]*T[0]'(X)+A[1]*T[1]'(X) ... +A[NP-1]*T[NP-1]'(X)] 
 0.119 0.147 0.299E-01 -0.107E-02 0.245E-02 
;
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_all         0.0343
_refine_ls_wR_factor_gt          0.0323
_refine_ls_wR_factor_ref         0.0323
_reflns_limit_h_max              16
_reflns_limit_h_min              -16
_reflns_limit_k_max              13
_reflns_limit_k_min              -14
_reflns_limit_l_max              17
_reflns_limit_l_min              0
_reflns_number_gt                8393
_reflns_number_total             8550
_reflns_threshold_expression     I>2.0\s(I)
_oxford_diffrn_Wilson_B_factor   2.15
_oxford_diffrn_Wilson_scale      28.79
_oxford_refine_ls_scale          0.18860(17)
_cod_data_source_file            d4md00422a2.cif
_cod_data_source_block           I_CCDC2
_cod_depositor_comments
;
The following automatic conversions were performed:

data item '_exptl_crystal_density_meas' value 'not measured' was
changed to '?' -- the value is perceived as not measured.

Automatic conversion script
Id: cif_fix_values 8170 2020-07-09 18:12:32Z antanas 
;
_cod_original_sg_symbol_H-M      'P 21'
_cod_database_code               7249173
_oxford_refine_reflns_threshold_expression I>2.0\s(I)
_refine_ls_r_factor_ref          0.0249
_reflns_number_all               8550
_oxford_hooft_y                  0.042(6)
_oxford_bijvoet_difference       0.035(4)
_oxford_refined_flack_x          0.037(12)