Modeling process

Preparation of the library drugs and targets

We used GPCR SARfari database as our training datasets. GPCR SARfari is a public, web-accessible database of measured binding affinities, focusing chiefly on the interactions of GPCR proteins considered to be candidate chemical-GPCR with chemicals that are small, drug-like molecules. Activity data were filtered to keep only activity end-point points that had half-maximum inhibitory concentration (IC50), half-maximum effective concentration (EC50) or Ki values. Herein, to ensure that enough number of molecules could be used in model building, we previously selected those targets with larger than 75 biological activity data. Following this procedure, 112,434 compounds associated with 237 target proteins remained with 222,020 activity end-points, which were used for model building.

Preparation of the positive and negative set

For those compounds with more than one activity values, we took the mean value of their activity values as the final activity value. A compound was considered active when the mean activity value was below 10 uM. All compounds higher than 10 uM are considered inactive. Following this split, maybe some human proteins have very little number of negative samples. To balance the number between positive samples and negative samples for each human protein, we randomly selected certain number of compounds from other human proteins to generate the negative samples for these human proteins. The number of these selected negative samples together with inactive samples should be basically equal to the number of the active samples for these human proteins. These prepared positive set and negative set were used as the subsequent model building. The SMILES formats of the compounds involved in the positive set and negative set for each human protein could be downloaded from the GPCRnet website.

Model training and validation

A series of high confidence QSAR models were built using GPCR SARfari. Naïve Bayes models were built with different fingerprint representations for 237 GPCR proteins. The Naïve Bayes method for predicting DTI profiling was chosen as it provided both good performance for noisy data sets and a high speed of calculation. Herein, to obtain the best model performance, we compared 11 types of molecular fingerprints when establishing the prediction models, including FP2, MACCS, FP3, FP4, Daylight, ECFP2-1024, ECFP4-1024, ECFP6-1024, ECFP2-2048, ECFP4-2048, and ECFP6-2048. To obtain the better prediction ability, we also ensemble all fingerprint models to obtain the average output. For each model, we applied five-fold cross validation and external validation to evaluate the prediction performance of models. For 5-fold cross validation, the data set is split into 5 roughly equal-sized parts firstly, and then we fit the model to four parts of the data and calculate the error rate of the other part. The process is repeated 5 times so that every part can be predicted as a validation set. To observe the stability of models, we repeated the cross validation program 10 times to report standard deviations of each statistics. For the external validation, the data were split in two parts for the validation step: compounds were clustered and assigned a cluster number. Clusters with an odd number were assigned to the test set, and the clusters with an even number were assigned to the training set. Models were built with the training set, and the test set was scored. Finally, a model was built with all data and scored against itself – the training set and whole set should provide similar validation statistics. Statistics on the performance of the models were reported, including commonly used ones in classification schemes: accuracy, sensitivity, specificity, AUC, Matthews correlation coefficient (MCC) and F-score values. The cut-off providing the best MCC value was adopted, as they are shown to provide better performance. Furthermore, two analyses were used to assess the performance of the different models. The first analysis provides an overall score and does not need to specify a cut-off for distinguishing active from inactive compounds. The area under the receiver operating characteristic (ROC) curve provides an indication of the ability of the model to prioritize active compounds over inactive compounds. The ROC curve is the plot of the true positive versus the false positive rate.

  Model Performance


ROC curves
  GPCR targets
click the links below to view all corresponding targets

Models using different types of fingerprints

The 237 GPCR targets
Uniprot_ID Variant_Name Protein Details
P61169 rDRD2_1559 D(2) dopamine receptor View
P14416 hDRD2_94 D(2) dopamine receptor View
P19327 r5HT1A_1377 5-hydroxytryptamine receptor 1A View
P41145 hOPRK1_173 Kappa-type opioid receptor View
P35372 hOPRM1_166 Mu-type opioid receptor View
P29274 hAA2A_129 Adenosine receptor A2a View
P43140 rA1AA_1499 Alpha-1A adrenergic receptor View
P23944 rA1AD_1393 Alpha-1D adrenergic receptor View
P41143 hOPRD1_172 Delta-type opioid receptor View
P30542 hAA1_135 Adenosine receptor A1 View
P08908 h5HT1A_89 5-hydroxytryptamine receptor 1A View
P15823 rA1AB_1367 Alpha-1B adrenergic receptor View
P35462 hDRD3_170 D(3) dopamine receptor View
P21554 hCB1R_102 Cannabinoid receptor 1 View
P14842 r5HT2A_1365 5-hydroxytryptamine receptor 2A View
P34972 hCB2R_158 Cannabinoid receptor 2 View
P33535 rOPRM1_1462 Mu-type opioid receptor View
P33765 hAA3_156 Adenosine receptor A3 View
Q9Y5N1 hHRH3_290 Histamine H3 receptor View
Q99705 hGPR24_245 Melanin-concentrating hormone receptor 1 View
P25099 rAA1_1397 Adenosine receptor A1 View
P28223 h5HT2A_125 5-hydroxytryptamine receptor 2A View
P28335 h5HT2C_126 5-hydroxytryptamine receptor 2C View
P25103 hNK1R_118 Substance-P receptor View
P32245 hMC4R_148 Melanocortin receptor 4 View
P30543 rAA2A_1416 Adenosine receptor A2a View
P33533 rOPRD1_1460 Delta-type opioid receptor View
P21917 hDRD4_106 D(4) dopamine receptor View
P50406 h5HT6_209 5-hydroxytryptamine receptor 6 View
P29275 hAA2B_130 Adenosine receptor A2b View
P51681 hCCR5_213 C-C chemokine receptor type 5 View
P29089 rAGTR1B_1412 Type-1B angiotensin II receptor View
P08909 r5HT2C_1356 5-hydroxytryptamine receptor 2C View
P35348 hA1AA_162 Alpha-1A adrenergic receptor View
P35368 hA1AB_164 Alpha-1B adrenergic receptor View
P30556 hAGTR1A_137 Type-1 angiotensin II receptor View
P08482 rCHRM1_1353 Muscarinic acetylcholine receptor M1 View
P11229 hCHRM1_92 Muscarinic acetylcholine receptor M1 View
P19328 rA2AB_1378 Alpha-2B adrenergic receptor View
P08172 hCHRM2_86 Muscarinic acetylcholine receptor M2 View
P22909 rA2AA_1391 Alpha-2A adrenergic receptor View
Q9QYN8 rHRH3_1207 Histamine H3 receptor View
P22086 rA2AC_1390 Alpha-2C adrenergic receptor View
P32239 hCCKBR_147 Gastrin/cholecystokinin type B receptor View
P20272 rCB1R_1379 Cannabinoid receptor 1 View
P25105 hPAFR_119 Platelet-activating factor receptor View
P30968 hGNRHR_142 Gonadotropin-releasing hormone receptor View
P25101 hETA_117 Endothelin-1 receptor View
P20309 hCHRM3_98 Muscarinic acetylcholine receptor M3 View
P41146 hOPRL1_174 Nociceptin receptor View
P25100 hA1AD_116 Alpha-1D adrenergic receptor View
P10980 rCHRM2_1361 Muscarinic acetylcholine receptor M2 View
P30994 r5HT2B_1446 5-hydroxytryptamine receptor 2B View
P28221 h5HT1D_123 5-hydroxytryptamine receptor 1D View
P18901 rDRD1_1375 D(1A) dopamine receptor View
P25095 rAGTR1A_1396 Type-1A angiotensin II receptor View
P13945 hB3AR_93 Beta-3 adrenergic receptor View
P41595 h5HT2B_176 5-hydroxytryptamine receptor 2B View
P08588 hB1AR_88 Beta-1 adrenergic receptor View
P28222 h5HT1B_124 5-hydroxytryptamine receptor 1B View
Q15761 hNPY5R_231 Neuropeptide Y receptor type 5 View
P30551 rCCKAR_1422 Cholecystokinin receptor type A View
P08483 rCHRM3_1354 Muscarinic acetylcholine receptor M3 View
P35367 hHRH1_163 Histamine H1 receptor View
P07550 hB2AR_84 Beta-2 adrenergic receptor View
P19020 rDRD3_1376 D(3) dopamine receptor View
P32300 mOPRD1_1455 Delta-type opioid receptor View
P35351 rAGTR2_1474 Type-2 angiotensin II receptor View
P21452 hNK2R_99 Substance-K receptor View
P08485 rCHRM4_1355 Muscarinic acetylcholine receptor M4 View
P30969 rGNRHR_1443 Gonadotropin-releasing hormone receptor View
P32238 hCCKAR_146 Cholecystokinin receptor type A View
P41597 hCCR2_177 C-C chemokine receptor type 2 View
Q92847 hGHSR_238 Growth hormone secretagogue receptor type 1 View
P29276 rAA2B_1413 Adenosine receptor A2b View
P34969 h5HT7_157 5-hydroxytryptamine receptor 7 View
P21731 hTBXA2R_105 Thromboxane A2 receptor View
P24530 hETBR_110 Endothelin B receptor View
P51677 hCCR3_211 C-C chemokine receptor type 3 View
P08911 rCHRM5_1357 Muscarinic acetylcholine receptor M5 View
Q9Y271 hCYSLTR1_287 Cysteinyl leukotriene receptor 1 View
P08913 hA2AA_91 Alpha-2A adrenergic receptor View
P26684 rETA_1403 Endothelin-1 receptor View
P48039 hMTNR1A_197 Melatonin receptor type 1A View
P35346 hSSTR5_161 Somatostatin receptor type 5 View
P25929 hNPY1R_122 Neuropeptide Y receptor type 1 View
P30874 hSSTR2_140 Somatostatin receptor type 2 View
P49286 hMTNR1B_203 Melatonin receptor type 1B View
P34995 hPTGER1_160 Prostaglandin E2 receptor EP1 subtype View
P21728 hDRD1_103 D(1A) dopamine receptor View
P32745 hSSTR3_154 Somatostatin receptor type 3 View
P18825 hA2AC_97 Alpha-2C adrenergic receptor View
P46663 hBDKRB1_190 B1 bradykinin receptor View
P50052 hAGTR2_207 Type-2 angiotensin II receptor View
P08173 hCHRM4_87 Muscarinic acetylcholine receptor M4 View
P41144 cavOPRK1_1491 Kappa-type opioid receptor View
Q9H244 hP2RY12_263 P2Y purinoceptor 12 View
P37288 hAVPR1A_171 Vasopressin V1a receptor View
P41968 hMC3R_178 Melanocortin receptor 3 View
P31391 hSSTR4_145 Somatostatin receptor type 4 View
P21453 hEDG1_100 Sphingosine 1-phosphate receptor 1 View
P08912 hCHRM5_90 Muscarinic acetylcholine receptor M5 View
P49682 hCXCR3_204 C-X-C chemokine receptor type 3 View
P97266 cavOPRM1_1580 Mu-type opioid receptor View
P30872 hSSTR1_139 Somatostatin receptor type 1 View
P30559 hOXTR_138 Oxytocin receptor View
P28190 bAA1_1406 Adenosine receptor A1 View
P30411 hB2R_133 B2 bradykinin receptor View
Q01726 hMC1R_219 Melanocyte-stimulating hormone receptor View
Q15722 hLTB4R_248 Leukotriene B4 receptor 1 View
P56481 mCCKBR_1547 Gastrin/cholecystokinin type B receptor View
P34975 rOPRK1_1467 Kappa-type opioid receptor View
P43115 hPTGER3_180 Prostaglandin E2 receptor EP3 subtype View
P25116 hPAR1_121 Proteinase-activated receptor 1 View
Q9H3N8 hHRH4_264 Histamine H4 receptor View
P30729 rDRD4_1431 D(4) dopamine receptor View
Q9Y5Y4 hGPR44_293 Prostaglandin D2 receptor 2 View
P18089 hA2AB_96 Alpha-2B adrenergic receptor View
P28564 r5HT1B_1408 5-hydroxytryptamine receptor 1B View
P29371 hNK3R_131 Neuromedin-K receptor View
P30560 rAVPR1A_1428 Vasopressin V1a receptor View
P25025 hIL8RB_113 C-X-C chemokine receptor type 2 View
O43613 hHCRTR1_69 Orexin receptor type 1 View
P30518 hV2R_134 Vasopressin V2 receptor View
P33032 hMC5R_155 Melanocortin receptor 5 View
P25115 rDRD5_1400 D(1B) dopamine receptor View
Q13639 h5HT4_223 5-hydroxytryptamine receptor 4 View
Q9NS75 hCYSLTR2_274 Cysteinyl leukotriene receptor 2 View
Q13258 hPTGDR_220 Prostaglandin D2 receptor View
P70536 rOXTR_1566 Oxytocin receptor View
Q00788 rV2R_1592 Vasopressin V2 receptor View
Q99500 hEDG3_239 Sphingosine 1-phosphate receptor 3 View
Q9UKP6 hGPR14_283 Urotensin-2 receptor View
O95977 hEDG6_79 Sphingosine 1-phosphate receptor 4 View
P30553 rCCKBR_1424 Gastrin/cholecystokinin type B receptor View
P42866 mOPRM1_1495 Mu-type opioid receptor View
Q01727 mMC1R_1596 Melanocyte-stimulating hormone receptor View
P32246 hCCR1_149 C-C chemokine receptor type 1 View
P32305 r5HT7_1457 5-hydroxytryptamine receptor 7 View
O43614 hHCRTR2_70 Orexin receptor type 2 View
P35408 hPTGER4_167 Prostaglandin E2 receptor EP4 subtype View
Q8TDS4 hHM74a_31 Hydroxycarboxylic acid receptor 2 View
P25104 bAGTR1A_1399 Type-1 angiotensin II receptor View
P20288 bDRD2_1380 D(2) dopamine receptor View
P28565 r5HT1D_1409 5-hydroxytryptamine receptor 1D View
P49146 hNPY2R_201 Neuropeptide Y receptor type 2 View
P35463 susETBR_1489 Endothelin B receptor View
Q29010 susETA_1609 Endothelin-1 receptor View
P28647 rAA3_1411 Adenosine receptor A3 View
P51050 ggMTNR1B_1530 Melatonin receptor type 1B View
P61073 hCXCR4_144 C-X-C chemokine receptor type 4 View
P49285 ggMTNR1A_1520 Melatonin receptor type 1A View
P49288 ggMtr1c_1522 Melatonin receptor type 1C View
P30940 r5HT1F_1440 5-hydroxytryptamine receptor 1F View
Q9NPC1 hLTB4R2_268 Leukotriene B4 receptor 2 View
P18130 bA1AA_1372 Alpha-1A adrenergic receptor View
P28646 rSSTR1_1410 Somatostatin receptor type 1 View
P48974 rAVPR1B_1518 Vasopressin V1b receptor View
P21730 hC5R1_104 C5a anaphylatoxin chemotactic receptor 1 View
P47936 mCB2R_1512 Cannabinoid receptor 2 View
P25021 hHRH2_111 Histamine H2 receptor View
P47901 hAVPR1B_196 Vasopressin V1b receptor View
P18090 rB1AR_1371 Beta-1 adrenergic receptor View
Q9H228 hEDG8_262 Sphingosine 1-phosphate receptor 5 View
P51679 hCCR4_212 C-C chemokine receptor type 4 View
P21451 rETBR_1384 Endothelin B receptor View
P25024 hIL8RA_112 C-X-C chemokine receptor type 1 View
P41149 mMC5R_1492 Melanocortin receptor 5 View
O95136 hEDG5_77 Sphingosine 1-phosphate receptor 2 View
P21918 hDRD5_107 D(1B) dopamine receptor View
P43119 hPTGIR_182 Prostacyclin receptor View
O14842 hGPR40_59 Free fatty acid receptor 1 View
P33534 mOPRK1_1461 Kappa-type opioid receptor View
Q95136 bDRD1_1293 D(1A) dopamine receptor View
P30680 rSSTR2_1429 Somatostatin receptor type 2 View
O43193 hGPR38_66 Motilin receptor View
P47900 hP2RY1_195 P2Y purinoceptor 1 View
P30557 mPTGER3_1426 Prostaglandin E2 receptor EP3 subtype View
P43116 hPTGER2_181 Prostaglandin E2 receptor EP2 subtype View
P47898 h5HT5A_194 5-hydroxytryptamine receptor 5A View
P56450 mMC4R_1545 Melanocortin receptor 4 View
P26255 rB3AR_1402 Beta-3 adrenergic receptor View
P14600 rNK1R_1364 Substance-P receptor View
P31389 cavHRH1_1448 Histamine H1 receptor View
P06199 susCHRM2_1352 Muscarinic acetylcholine receptor M2 View
Q28838 bA2AA_1607 Alpha-2A adrenergic receptor View
P30989 hNTSR1_143 Neurotensin receptor type 1 View
Q62758 r5HT4_1029 5-hydroxytryptamine receptor 4 View
P51685 hCCR8_215 C-C chemokine receptor type 8 View
P54833 cB2AR_1543 Beta-2 adrenergic receptor View
P34968 m5HT2C_1464 5-hydroxytryptamine receptor 2C View
P50130 susDRD1_1529 D(1A) dopamine receptor View
P41231 hP2RY2_175 P2Y purinoceptor 2 View
P30939 h5HT1F_141 5-hydroxytryptamine receptor 1F View
Q02152 m5HT2B_1598 5-hydroxytryptamine receptor 2B View
P32247 hBRS3_150 Bombesin receptor subtype-3 View
P35363 m5HT2A_1475 5-hydroxytryptamine receptor 2A View
Q9Y2T6 hGPR55_289 G-protein coupled receptor 55 View
Q969V1 hMCHR2_28 Melanin-concentrating hormone receptor 2 View
P31390 rHRH1_1449 Histamine H1 receptor View
P34976 orAGTR1A_1468 Type-1 angiotensin II receptor View
Q9QZN9 rCB2R_1208 Cannabinoid receptor 2 View
Q63931 cavCCKAR_1038 Cholecystokinin receptor type A View
P61168 mDRD2_1558 D(2) dopamine receptor View
P28336 hNMBR_127 Neuromedin-B receptor View
P43088 hPTGFR_179 Prostaglandin F2-alpha receptor View
Q9JI35 cavHRH3_1189 Histamine H3 receptor View
Q8TDU6 hBG37_45 G-protein coupled bile acid receptor 1 View
P79291 susOPRD1_1574 Delta-type opioid receptor View
P30938 rSSTR5_1439 Somatostatin receptor type 5 View
P28566 h5HT1E_128 5-hydroxytryptamine receptor 1E View
Q969F8 hGPR54_40 KiSS-1 receptor View
P16610 rNK2R_1370 Substance-K receptor View
Q923Y8 mTA1_1148 Trace amine-associated receptor 1 View
P30937 rSSTR4_1438 Somatostatin receptor type 4 View
P33033 mMC3R_1459 Melanocortin receptor 3 View
Q75Z89 b5HT2A_1254 5-hydroxytryptamine receptor 2A View
Q9UBY5 hEDG7_35 Lysophosphatidic acid receptor 3 View
Q15077 hP2RY6_227 P2Y purinoceptor 6 View
P49019 hHM74_200 Hydroxycarboxylic acid receptor 3 View
Q8JZL2 mGPR24_1114 Melanin-concentrating hormone receptor 1 View
P32240 mPTGER4_1452 Prostaglandin E2 receptor EP4 subtype View
P49684 rGPR14_1526 Urotensin-2 receptor View
P47746 mCB1R_1507 Cannabinoid receptor 1 View
P79400 sus5HT1D_1577 5-hydroxytryptamine receptor 1D View
P21462 hFPR1_101 fMet-Leu-Phe receptor View
Q16581 hC3AR1_234 C3a anaphylatoxin chemotactic receptor View
O88319 mNTSR1_1338 Neurotensin receptor type 1 View
Q62053 mPTGER2_1027 Prostaglandin E2 receptor EP2 subtype View
Q9HBW0 hEDG4_53 Lysophosphatidic acid receptor 2 View
P35377 mOPRL1_1481 Nociceptin receptor View
Q92633 hEDG2_237 Lysophosphatidic acid receptor 1 View
P48145 hGPR7_198 Neuropeptides B/W receptor type 1 View
Q91ZY1 rHRH4_1289 Histamine H4 receptor View
P35370 rOPRL1_1478 Nociceptin receptor View
O08786 mCCKAR_1311 Cholecystokinin receptor type A View
O54798 mBRS3_1326 Bombesin receptor subtype-3 View

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