Undesirable moieties and substructures involved in toxicity problems.

     For some of them, according to reports in the literature and a structural analysis of approved drugs, we decided to apply a threshold cutoff on the number of occurrences of a given substructure in the same compound.
      For instance we accept up to 3 nitro groups (although nitro are well-known structural alerts) because several approved drugs have a nitro group and because this group can be replaced during optimization (72).

Depending on such analysis, the molecule is then categorized in three baskets or to the PAINS basket:

      • Accepted

      Compounds with no structural alerts and satisfying the physicochemical filter.

      • Intermediate
      Compounds which embeds low-risk structural alerts with a number of occurrences below the threshold.
      (the notion of low risk structural alerts has to be considered within the context of the project, the type of diseases...).

      • Rejected
      Compounds that do not pass the selected or user defined physicochemical filter.
      Compounds that that include a high-risk structural alert and/or exceed the threshold of occurrence of low-risk structural alerts.



      • PAINS
      Compounds flagged due to the presence of some chemical groups that belong to the PAINS category.



       C = Aliphatic Carbon , c = Aromatic Carbon, * = Any Atom

Substructure 2D Depiction Rejection Threshold References
1_2_aminothiazole  1 44
1_2_dicarbonyl_oxalyl  0 55, 56, 58
1_2_thiazol_3_one  1 63
1_aminobenzotriazole  1 65
2_phenylbenzimidazole  1 44, 6
3_amino_9_ethylcarbazoles  1 66
4_subst_n_alkyltetrahydropyridines  1 44
4_vinyl_pyridine  no limit 61
6_membered_aromatic_sulfur_NSN  0 73
6_membered_aromatic_sulfur_NSC  1 73
6_membered_aromatic_sulfur_CSN  1 73
6_membered_aromatic_sulfur_CSC  1 73
9_aminoacridine  1 44, 6
acetal_1_in_ring  1 53
acetal_both_in_ring  1 53
acetylene_alkyne  1 44, 58
acrylamide  1 23, 56
acyclic_acetal  no limit 67
acyclic_acid_halide_acyl_halide  0 55
acyl_amide  1 56, 58, 59
acyl_cyanides  0 31
acyl_isoamide_aromatic  1 53
adamantane  1 53
aldehyde  0 53, 55, 58, 60, 61
aliphatic_ketone  0 18, 44
alkyl_halide_I  1 56
alkyl_halide_Cl_Br  1 56
alphahalo_ketone_carbonyl  0 55
anhydride  0 55
anthracene  1 23, 55, 63
azide  1 31, 55, 60
aziridine  0 18, 55, 60, 62
azo  1 60, 63
azocyanamide  1 64
beta_heterosubstituted_carbonyl  1 55, 56
betalactams  1 18
carbamic_acid  no limit 23
carbazide  0 64
carbodiimide  1 55, 63
catechol  1 58, 6
chloramidine  1 64
consecutive_alkyl_chains  0 44, 6
coumarines  1 44, 6
cyanohydrins  0 63
cyanophosphonate  1 64
cyclic_crown_2_2  1 31, 53, 60
cyclic_crown_2_3  1 53
cyclic_crown_3_3  1 53
diazonium  1 31, 56, 57, 63
ellipticine  1 44, 6
enamine  no limit 23, 53
epoxide  0 18, 56, 58
fmoc  1 53
formic_acid_esters  1 63
furocoumarines  1 44, 6
halo_alkene  no limit 60, 55
halo_amine  no limit 68
halogenure  5
halogenure_F  7
halopyrimidine  0 18
hemiaminal  no limit 23, 53
hemiketal  no limit 64
heteroatom_heteroatom_N_N  0 18
heteroatom_heteroatom_N_S  0 18
heteroatom_heteroatom_O_N  0 18
heteroatom_heteroatom_S_O  0 18
heteroatom_heteroatom_S_S  0 18
hydantoin  1 44
hydralazine  1 44
hydrazide  1 56, 57
hydrazine  no limit 56, 57
hydrazone  no limit 56, 57
hydroxamic_acid  no limit 44
hydroxylamine  no limit 44, 56
imidazole  1 44
imide  1 56, 57
imidoyl_halide  no limit 55
imine_C  0 44
imine_c_arom  no limit 44
isocyanate  no limit 60
isocyanide_isonitrile  no limit 44
isothiocyanate  0 60
lawesson_reagent_derivative  1 64
maleimide  no limit 23, 53
meta_aminophenol  0 55, 56, 58, 61
michael_acceptors  0 18, 44, 53, 63, 64
mustard_gas  1 66
nitramine  1 63
nitro  3 55, 58, 60, 61
nitroso  no limit 60
ortho_aminophenol  0 55, 56, 58, 61
ortho_aniline  0 44
ortho_hydroxyanilines  1 44
orthonitrophenyl_ester  1 66
orthoquinone  0 44
oxime  1 56, 57
oxonium  no limit 31
para_aminophenol  0 55, 56, 58, 61
para_hydroquinone  0 44
para_hydroxyanilines  1 44
para_para_dihydroxybiphenyl  1 63
para_para_dihydroxystilbene  1 63
paranitrophenyl_ester  1 64
pentafluorophen_ester  1 64
perhaloketone  0 18
peroxide  0 31, 44, 60
phenanthrene_het_N_C  1 53
phenanthrene_het_C_N  1 53
phenanthrene_het_N_N  1 53
phenol  5 31, 44, 60
phosphorane  1 44
phosphonic_acid  6 53
polyenes  no limit 31
propiolactone  1 44, 6
propiosultone  1 44, 6
quinone  0 44
sulfonate_ester  0 44, 55
sulfonic_acid  no limit 44, 55
sulfonic_acid_ester  1 44, 55
sulfonium  1 31, 53, 66
sulfonyl_cyanide  0 55
sulfonyl_halide  0 55
sulfonyl_urea  1 56
sulfoxide  no limit 44, 6
sulphanylamino  1 64
thiazolidinedione  1 44
thioacetal  no limit 44
thiocarbamate  no limit 44
thioester  1 53
thioic_acid  1 63
thioketone  1 63
thiol  1 44
thiophene  1 44
toxoflavins  1 66
triacyloxime  1 64
triazenes  1 60, 66
triflate  1 63, 64
triphenyl  1 53



» Frequents Hitters according to Roche et al. [20].
Compounds which show up as hits in many different biological assays covering a wide range of targets, because of the activity of the compound is not specific for the target and/or the compound perturbs the assay or the detection method. Compounds which contains that kind of moieties are poor starting points for drug discovery programs and in general must be removed, Thus, the default value allowed for the substructures/compounds is set to 0

Substructure 2D Depiction Default Value
Apomorphine   0
Benserazide   0
Calciferol   0
Clofazimine   0
Dextrotiroxina   0
Dextrotiroxina-sodica 0
Diethylstilbestrol   0
Dopamine   0
Fenoterol   0
Idebenone   0
Methyldopamine   0
SF85190   0
Tocopherol   0
Triazolam   0
Troglitazone   0


» Aggregators according to McGovern et al. [21].
Aggregators are nonspecific compounds susceptible to form submicrometer aggregates. It has been suggested that this aggregate species is responsible for the inhibition of many different enzymes. Compounds which contains that kind of moieties must be removed. Thus, the default value allowed for the substructures/compounds is set to 0

Substructure 2D depiction Default Value
1_01   0
1_02   0
1_03   0
1_04   0
1_05   0
1_06   0
1_07   0
1_08   0
1_09   0
1_10   0
1_11   0
1_12   0
1_13_2   0
2_01   0
2_02   0
2_03   0
2_04   0
2_05   0
2_06   0
2_07   0
2_08   0
2_09   0
2_10   0
2_11   0
2_12   0
2_13   0
2_14   0
2_15   0
2_16   0
2_17   0
2_18_3   0
2_19   0
2_20   0
Benzyl_benzoate   0
Bisindolylmalemide_i   0
Clotrimazole   0
Delavirdine   0
Econazole   0
Indigo   0
Indirubin   0
K252c   0
Miconazole   0
Nicardipine   0
Quercetin   0
Ro318220   0
Rottlerin   0
Sulconazole   0
U0126   0


» Pan Assay Interference compoundS (PAINS). The PAINS structures are not listed here, please see Baell et al. publication Supporting Information Tables and Figures [23] and the dedicated page