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_7249171
_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         'C21 H21 F N6 O6, C2 H3 N, 0.1(H2 O)'
_chemical_formula_sum            'C23 H24.2 F N7 O6.1'
_chemical_formula_weight         515.29
_chemical_name_systematic
'methyl 5-((3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamido)-2-fluorobenzoate'
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_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                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   7.9953(2)
_cell_length_b                   15.3161(4)
_cell_length_c                   19.6255(5)
_cell_measurement_reflns_used    9893
_cell_measurement_temperature    180
_cell_measurement_theta_max      70.0629
_cell_measurement_theta_min      3.6607
_cell_volume                     2403.28(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      180
_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  0.036
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       18
_diffrn_reflns_limit_k_min       -18
_diffrn_reflns_limit_l_max       21
_diffrn_reflns_limit_l_min       -23
_diffrn_reflns_number            28864
_diffrn_reflns_theta_full        68.208
_diffrn_reflns_theta_max         68.208
_diffrn_reflns_theta_min         3.661
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.940
_exptl_absorpt_correction_T_max  0.95
_exptl_absorpt_correction_T_min  0.82
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details   'SADABS (Siemens, 1996)'
_exptl_crystal_colour            colourless
_exptl_crystal_density_diffrn    1.424
_exptl_crystal_density_meas      ?
_exptl_crystal_density_method    'not measured'
_exptl_crystal_description       plate
_exptl_crystal_F_000             1076
_exptl_crystal_size_max          0.466
_exptl_crystal_size_mid          0.178
_exptl_crystal_size_min          0.058
_refine_diff_density_max         0.25
_refine_diff_density_min         -0.19
_refine_ls_abs_structure_details
; 
 Parsons, Flack & Wagner (2013), 
 1591 Friedel Pairs 
;
_refine_ls_abs_structure_Flack   0.08(3)
_refine_ls_extinction_coef       60(4)
_refine_ls_extinction_method     'Larson (1970), Equation 22'
_refine_ls_goodness_of_fit_ref   0.9432
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     345
_refine_ls_number_reflns         4270
_refine_ls_number_restraints     0
_refine_ls_R_factor_all          0.0327
_refine_ls_R_factor_gt           0.0313
_refine_ls_shift/su_max          0.0007120
_refine_ls_shift/su_mean         0.0000799
_refine_ls_structure_factor_coef F
_refine_ls_weighting_details
;
 Method, part 1, Chebychev polynomial, (Watkin, 1994, Prince, 1982) 
 [weight] = 1.0/[A~0~*T~0~(x)+A~1~*T~1~(x) ... +A~n-1~]*T~n-1~(x)] 
 where A~i~ are the Chebychev coefficients listed below and x= Fcalc/Fmax 
 Method = Robust Weighting (Prince, 1982) 
 W = [weight] * [1-(deltaF/6*sigmaF)^2^]^2^ 
 A~i~ are: 
 0.162 0.141 0.503E-01 
;
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_all         0.0333
_refine_ls_wR_factor_gt          0.0311
_refine_ls_wR_factor_ref         0.0311
_reflns_limit_h_max              9
_reflns_limit_h_min              -9
_reflns_limit_k_max              18
_reflns_limit_k_min              0
_reflns_limit_l_max              23
_reflns_limit_l_min              0
_reflns_number_gt                4270
_reflns_number_total             4409
_reflns_threshold_expression     I>2.0\s(I)
_oxford_diffrn_Wilson_B_factor   2.20
_oxford_diffrn_Wilson_scale      51.08
_oxford_refine_ls_scale          0.13698(17)
_cod_data_source_file            d4md00422a2.cif
_cod_data_source_block           I
_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_formula_sum        'C23 H24.20 F N7 O6.10'
_cod_database_code               7249171
_oxford_refine_reflns_threshold_expression I>2.0\s(I)
_refine_ls_r_factor_ref          0.0313
_reflns_number_all               4409
_oxford_hooft_y                  0.13(5)
_oxford_bijvoet_difference       0.08(3)
_oxford_refined_flack_x          0.10(11)