Model for High-Throughput Screening of Endocrine Disruptor and Method for Screening Same

1. A method for high-throughput screening of endocrine disruptors, comprising the following steps: step 1: acquisition of structural data selecting chemical structures of target compounds without relevant activity data from a public database, and denoting the chemical structures by SMILES numbers; step 2: determination of a target nuclear receptor determining a target nuclear receptor based on the disrupting activity of the target compounds to be predicted; step 3: matching of primary structural alerts selecting a target nuclear receptor high-throughput screening model based on the determined target nuclear receptor, calculating molecular fingerprints of the target compounds by using a PubChem fingerprints molecular fingerprint database of PaDEL-Descriptor software, and matching a calculated result with primary structural alerts of the target nuclear receptor high-throughput screening model, wherein the primary structural alerts are extracted through substructure frequency analysis and substructure percentage analysis; step 4: matching of secondary structural alerts grouping target compounds meeting the primary structural alerts based on the primary structural alerts, and matching the target compounds with secondary structural alerts of the target nuclear receptor high-throughput screening model by using SARpy software; and step 5: matching of tertiary structural alerts grouping target compounds meeting both the primary structural alerts and the secondary structural alerts based on the secondary structural alerts, and matching with tertiary structural alerts of the target nuclear receptor high-throughput screening model by using the SARpy software.

2. The method for high-throughput screening of endocrine disruptors according to claim 1, wherein a method for grouping the target compounds in step 4 comprises: grouping the primary structural alerts of the target nuclear receptor high-throughput screening model first, and taking the primary structural alerts containing polar atoms and aromatic ring bonds as Type 1; taking the primary structural alerts containing aromatic bonds as Type 2; taking the primary structural alerts of carbon chains containing oxygen atoms as Type 3; finally taking the primary structural alerts of any carbon chains without oxygen atoms and aromatic bonds as Type 4; wherein priorities of Type 1, Type 2, Type 3 and Type 4 are successively decreased, matching the primary structural alerts of the target compounds with the primary structural alerts in each group, and then classifying the target compounds from the group with successful matching to the group with the highest priority.

3. The method for high-throughput screening of endocrine disruptors according to claim 1, wherein a method for grouping the target compounds in step 5 comprises: grouping the secondary structural alerts of the target nuclear receptor high-throughput screening model first, and taking the secondary structural alerts existing only in antagonistic compounds as Type 1-1, taking the secondary structural alerts existing only in agonistic compounds as Type 1-2, and finally taking the secondary structural alerts existing in agonistic-antagonistic (A-Anta) compounds as Type 1-3; wherein priorities of Type 1-1, Type 1-2 and Type 1-3 are successively decreased, matching the secondary structural alerts of the target compounds with the secondary structural alerts in each group, and then classifying the target compounds from the group with successful matching to the group with the highest priority.

4. The method for high-throughput screening of endocrine disruptors according to claim 1, further comprising: step 6: analysis of ligand-receptor binding mode selecting target compounds meeting the primary structural alerts, the secondary structural alerts and the tertiary structural alerts through the target nuclear receptor high-throughput screening model, selecting a pattern protein receptor crystal from RCSB PDB Database based on the disrupting activity of the target compounds, performing molecular docking by using Autodock vina software, and performing ligand-receptor binding mode analysis by using Ligplus software; step 7: semi-quantitative prediction of binding activity and disrupting activity wherein target compounds with the same structural alert have similar ligand-receptor binding mode and similar binding activity; when the binding activity is positively correlated with the disrupting activity, grouping the target compounds based on the primary structural alerts, the secondary structural alerts and the tertiary structural alerts of the target compounds, and semi-quantitatively predicting the binding activity and the disrupting activity of the target compounds.

5. The method for high-throughput screening of endocrine disruptors according to claim 4, wherein the binding activity and the disrupting activity are standardized and classified in intensity by using formula, Activity ⁢ value = - log 10 ⁢ K i , K d , AC 50 , IC 50 , EC 50 ( uM ) 1000000 ; wherein Activity value denotes a value of activity intensity, Ki denotes an inhibition constant, Kd denotes a dissociation constant, AC50 denotes a median activity concentration, IC50 denotes a median inhibitory concentration, EC50 denotes a median effect concentration, uM denotes a micromolar weight, Activity value ≥7 denotes a strong activity intensity, 7>Activity value ≥6 denotes a medium activity intensity, and Activity value <6 denotes a weak activity intensity.

6. The method for high-throughput screening of endocrine disruptors according to claim 1, wherein the target nuclear receptor high-throughput screening model is anyone of an AR high-throughput screening model, an ERα high-throughput screening model and a GR high-throughput screening model.

7. The method for high-throughput screening of endocrine disruptors according to claim 3, wherein the target compounds are organic compounds.

8. The method for high-throughput screening of endocrine disruptors according to claim 1, wherein the target nuclear receptor is any one of androgen receptor (AR), estrogen receptor α (ER α) estrogen receptor β (ER β), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), retinoic acid receptor α (RAR α), retinoic acid receptor β (RAR β), retinoic acid receptor γ (RAR γ), thyroid hormone receptor α (TR α), thyroid hormone receptor β (TR β) and vitamin D receptor (VDR).

9. The method for high-throughput screening of endocrine disruptors according to claim 1, wherein the substructure frequency analysis is performed by using formula:, Frequency ⁢ of ⁢ a ⁢ fragment = ( N fragment A × N total ) ( N fragment ⁢ _ ⁢ total × N A ) , the substructure percentage analysis is performed by using formula, Percentage ⁢ of ⁢ a ⁢ fragment = N fragment A N A ⁢ or ⁢ N fragment I N I , wherein the above-mentioned Frequency of a fragment denotes substructure frequency; Percentage of a fragment denotes substructure percentage; NfragmentA is the number of active compounds containing the structural fragment; Ntotal is the total number of compounds in a whole data set; Nfragment_total is the total number of compounds containing the structural fragment; NA is the total number of active compounds in the data set; Nfragment is the total number of inactive compounds containing the structural fragment; and NI is the total number of inactive compounds in the data set.