Supporting Information

Home , Aesculin, Bakuchiol, Bergenin, Bulbocapnine, Cinobufagin, Dioscorine

How Many Traditional Chinese Medicine Components Have

Been Recognized by Modern Western Medicine? A

Chemoinformatic Analysis and Implications for Finding

Multicomponent Drugs

De-Xin Kong, Xue-Juan Li, Guang-Yan Tang and Hong-Yu Zhang

Table S1. Common agents in TCMD and CMC database. TCMD TCMD Name CMC number CMC Name number 8793 Serotonine MCMC00000036 SEROTONIN 3033 Dulcitol MCMC00000037 SORBITOL 7311 Noradrenaline MCMC00000052 NOREPINEPHRINE 3016 Dopamine MCMC00000060 DOPAMINE 9994 Tyramine MCMC00000062 TYRAMINE 4072 Glycine MCMC00000134 GLYCINE 4065 Glycerol MCMC00000141 GLYCERIN 813 L-Aspartic acid MCMC00000142 ASPARTIC ACID 380 Allyl isothiocyanate MCMC00000148 ALLYL ISOTHIOCYANATE 9078 Stearic acid MCMC00000151 STEARIC ACID 10032 Urea MCMC00000152 UREA 1237 Caffeine MCMC00000179 CAFFEINE 6687 2-Methyl-1,4-naphthoquinone MCMC00000187 MENADIONE 7615 Papaverine MCMC00000198 PAPAVERINE 7221 Nicotinic acid MCMC00000223 NIACIN 993 Benzyl ethyl alcohol MCMC00000229 PHENYLETHYL ALCOHOL 8204 Pyridoxine MCMC00000287 PYRIDOXINE 965 Benzoic acid MCMC00000292 BENZOIC ACID 7481 Orotic acid MCMC00000293 OROTIC ACID 2591 Dicoumarin MCMC00000296 DICUMAROL 10205 Vitamin A MCMC00000318 RETINOL 6026 D-Mannitol MCMC00000331 MANNITOL 8564 Salicylic acid MCMC00000332 SALICYLIC ACID 1693 Citric acid MCMC00000419 CITRIC ACID 10208 Vitamin B5 MCMC00000432 PANTOTHENIC ACID 5467 Khellin MCMC00000452 KHELLIN 9626 Theobromine MCMC00000463 THEOBROMINE 7843 Phytic acid MCMC00000465 PHYTIC ACID 8282 Quinicine MCMC00000478 VIQUIDIL

5614 Lapachol MCMC00000479 LAPACHOL 9664 Thymol MCMC00000517 THYMOL 8995 Sparteine MCMC00000522 SPARTEINE 5775 Lobeline MCMC00000526 LOBELINE 8129 D-Pseudoephedrine MCMC00000527 PSEUDOEPHEDRINE 9188 Synephrine MCMC00000552 SYNEPHRINE 3437 Eugenol MCMC00000582 EUGENOL 359 Allantoin MCMC00000584 ALLANTOIN 8208 Pyroglutamic acid MCMC00000589 PIDOLIC ACID 7219 Nicotinamide MCMC00000590 NIACINAMIDE 989 Benzyl alcohol MCMC00000599 BENZYL ALCOHOL 964 Benzaldehyde MCMC00000600 BENZALDEHYDE 6631 Methyl isobutyl ketone MCMC00000636 METHYL ISOBUTYL KETONE 8356 Resorcinol MCMC00000637 RESORCINOL 10016 10-Undecenoic acid MCMC00000649 UNDECYLENIC ACID 7399 Octadecanol MCMC00000650 STEARYL ALCOHOL 1583 Chrysazin MCMC00000683 DANTHRON 6754 Methyl salicylate MCMC00000695 METHYL SALICYLATE 990 Benzyl benzoate MCMC00000701 BENZYL BENZOATE 10084 Vanillin MCMC00000705 VANILLIN 4581 Hydroquinone MCMC00000720 HYDROQUINONE 1348 Caprylic acid MCMC00000725 OCTANOIC ACID 10043 Ursodeoxycholic acid MCMC00000767 URSODIOL 2985 2,6-Ditertbutyl-4-methyl phenol MCMC00000768 BUTYLATED HYDROXYTOLUENE 3356 Ethanolamine MCMC00000835 MONOETHANOLAMINE 7402 9(Z)-Octadecen-1-ol MCMC00000840 OLEYL ALCOHOL 429 p-Aminobenzoic acid MCMC00000880 AMINOBENZOIC ACID 8504 Rutin MCMC00000892 RUTIN 1441 Catechin MCMC00000898 CIANIDOL 10322 Xanthotoxin MCMC00000915 METHOXSALEN 7363 Novobiocin MCMC00000942 NOVOBIOCIN 1002 Berberine MCMC00000967 BERBERINE SULFATE 3711 Galanthamine MCMC00000998 GALANTAMINE 1349 Capsaicin MCMC00001027 CAPSAICINE 8352 Resibufogenin MCMC00001070 BUFOGENIN 3112 Ellagic acid MCMC00001113 ELLAGIC ACID 10203 Visnadin MCMC00001115 VISNADINE 5668 Leucocyanidin MCMC00001123 LEUCOCIANIDOL 3120 Emetine MCMC00001128 EMETINE 7343 Norpseudoephedrine MCMC00001150 CATHINE 5747 cis-9,cis-12-Linoleic acid MCMC00001184 GAMOLENIC ACID 1320 Cannabinol MCMC00001230 CANNABINOL 4903 Hypericin MCMC00001300 HYPERICIN

6746 D-N-Methyl-pseudoephedrine MCMC00001313 METHYLEPHEDRINE 2575 Dicaffeoylquinic acid MCMC00001729 CYNARINE 9508 DELTA9-Tetrahydrocannabinol MCMC00001742 DRONABINOL 7303 Nonoyl vanillylamide MCMC00001836 NONIVAMIDE 9459 Terpin MCMC00001838 TERPIN 4031 Glucosamine MCMC00001959 GLUCOSAMINE 9888 4,5',8-Trimethyl psoralen MCMC00002098 TRIOXSALEN 9585 Thalicarpine MCMC00002257 THALICARPINE 9986 Tylocrebrine MCMC00002446 TYLOCREBIN-(+) 5981 Malic acid MCMC00002450 MALIC ACID 214 Acronycine MCMC00002476 ACRONINE 1394 beta-Carotene MCMC00002511 BETA CAROTENE 10437 Zincpolyanemine MCMC00002705 PYRITHIONE ZINC 7326 Norephedrine MCMC00002809 PHENYLPROPANOLAMINE 3964 Glaziovine MCMC00002985 GLAZIOVINE 10083 Valtratum MCMC00003052 VALTRATE 2605 Didrovaltratum MCMC00003053 DIDROVALTRATE 8861 Silybin MCMC00003236 SILIBININ 196 Acevaltratum MCMC00003342 ACEVALTRATE 3350 Eseridine MCMC00003357 ESERIDINE 8863 Silydianin MCMC00003521 SILIDIANIN 470 Amygdalin MCMC00003522 AMYGDALIN(D) 8862 Silychristin MCMC00003659 SILICRISTIN 1451 D-Cathinone MCMC00004948 CATHINONE 9270 Taurine MCMC00005803 TAURINE 10349 Xylose MCMC00005835 XYLOSE 7325 Nordihyolroguaiaretic acid MCMC00005851 MASOPROCOL 7220 Nicotine MCMC00006141 NICOTINE 691 Arecoline MCMC00006149 ARECOLINE 7808 Phenylpropyl alcohol MCMC00006157 PHENYLPROPANOL 8526 Safrole MCMC00006158 SAFROLE 7932 Piperine MCMC00006159 PIPERINE 7776 Phenol MCMC00006163 PHENOL 891 Azelaic acid MCMC00006166 AZELAIC ACID 1008 Bergenin MCMC00006175 BERGENIN 7583 Palmitin MCMC00006180 TRIPALMITIN 10218 Vitamin U MCMC00006185 METHYLMETHIONINE SULFONIUM CHLORIDE 8590 Sanguinarine MCMC00006197 SANGUINARIUM CHLORIDE 4122 Gomisin A MCMC00006241 BESIGOMSIN 857 Atropine MCMC00006515 ATROPINE 8283 Quinidine MCMC00006519 QUINIDINE 8284 Quinine MCMC00006534 QUININE 3140 Ephedrine MCMC00006542 EPHEDRINE

9670 Tigloidine MCMC00006555 TROPIGLINE 2619 m-Digallic acid MCMC00006608 DIGALLOYL TRIOLEATE 432 gamma-Aminobutyric acid MCMC00006694 GAMMA-AMINOBUTYRIC ACID 6004 Maltose MCMC00006696 MALTOSE 1927 o-Cresol MCMC00006701 ORTHOCRESOL 7938 Piperonal MCMC00006706 PIPERONAL 3715 Gallic acid MCMC00006710 GALLIC ACID 7830 Phyllodulcin MCMC00006735 PHYLLODULCIN 7774 Phenethyl caffeate MCMC00006778 CAFFEIC ACID PHENETHYL ESTER 1871 Corticosterone MCMC00006906 CORTICOSTERONE 3354 Estriol MCMC00006909 ESTRIOL 3351 beta-Estradiol MCMC00006910 ESTRADIOL 1746 Cocaine MCMC00006911 COCAINE 784 Ascorbic acid MCMC00006918 ASCORBIC ACID 9661 Thymidine MCMC00006919 THYMIDINE 248 Adrenaline I MCMC00006922 EPINEPHRINE 3355 Estrone MCMC00006930 ESTRONE 6921 Morphine MCMC00006943 MORPHINE 7841 Physostigmine MCMC00006944 PHYSOSTIGMINE 8062 Progesterone MCMC00006945 PROGESTERONE 3281 Ergosterol MCMC00006947 ERGOSTEROL 1571 Cholesterol MCMC00006948 CHOLESTEROL 9482 Testosterone MCMC00006954 TESTOSTERONE 1057 Biotin MCMC00006956 BIOTIN 10212 Vitamin Ealpha MCMC00006959 VITAMIN E 3015 Dopa MCMC00006962 LEVODOPA 7779 Phenylalanine MCMC00006970 PHENYLALANINE 1772 Colchicine MCMC00006971 COLCHICINE 10209 Vitamin B12 MCMC00006978 CYANOCOBALAMINE 1298 Camphor MCMC00006987 CAMPHOR 1758 Codeine MCMC00006992 CODEINE 9272 Taurocholic acid MCMC00006998 TAUROCHOLIC ACID 1573 Cholic acid MCMC00006999 CHOLIC ACID 4898 Hyoscyamine MCMC00007009 HYOSCYAMINE 9620 Thebaine MCMC00007012 THEBAINE 1633 Cinchonine MCMC00007013 CINCHONINE 7074 alpha-Narcotine MCMC00007018 NOSCAPINE 8562 Salicin MCMC00007023 SALICIN 9998 Ubiquinone 10 MCMC00007037 UBIDECARENONE 1636 1,8-Cineole MCMC00007051 EUCALYPTOL 4087 Glycyrrhetinic acid MCMC00007052 ENOXOLONE 1770 Colchamine MCMC00007055 DEMECOLCINE 5422 Kainic acid MCMC00007056 KAINIC ACID

7973 Podophyllotoxin MCMC00007060 PODOPHYLLOTOXIN 2960 Diosmin MCMC00007062 DIOSMIN 1808 Conessine MCMC00007069 CONESSINE 8737 Securinine MCMC00007133 SECURININE 9852 3,5,3'-Triiodothyronine MCMC00007140 LIOTHYRONINE 1303 Camptothecin MCMC00007147 CAMPTOTHECIN 9146 Sucrose MCMC00007264 SUCROSE 5754 alpha-Lipoic acid MCMC00007273 THIOCTIC ACID 4429 Hesperidin MCMC00007282 HESPERIDIN 3596 Formaldehyde MCMC00007288 FORMALDEHYDE 4055 Glutathione MCMC00007294 GLUTATHIONE 2614 Diethylphthalate MCMC00007299 DIETHYL PHTHALATE 3662 Fumaric acid MCMC00007303 FUMARIC ACID 4563 Hydrastine MCMC00007308 HYDRASTINE 3373 Ethyl acetate MCMC00007312 ETHYL ACETATE 3851 Gentisic acid MCMC00007313 GENTISIC ACID 3297 Eriodictyol MCMC00007320 ERIODICTYOL 360 Allicin MCMC00007592 ALLICIN 1926 m-Cresol MCMC00007632 METACRESOL 4181 Guaiacol MCMC00007677 GUAIACOL 1546 Chicoric acid MCMC00007713 CICHORIC ACID 7931 Piperidine MCMC00007769 PIPERIDINE 1632 Cinchonidine MCMC00007810 CINCHONIDINE 2843 Diiodotyrosine MCMC00007825 DIOTYROSINE I 125 9491 1-Tetradecanol MCMC00007890 MYRISTYL ALCOHOL 8606 beta-Santonin MCMC00007922 SANTONIN 8436 Robustaflavone MCMC00008022 ROBUSTAFLAVONE 1662 Cinobufagin MCMC00008153 CINOBUFAGIN 1319 Cannabigerol MCMC00008159 (E)-2-(3,7-DIMETHYL-2,6-OCTA DIENYL)-5-PENTYL-1,3-BENZE NEDIOL 661 Arachidonic acid MCMC00008169 5,8,11,14-EICOSATETRAENOIC ACID 4092 Glycyrrhizic acid MCMC00008174 GLYCYRRHIZIN 2419 Demethylcoclaurine MCMC00008199 1-(P-HYDROXYBENZYL)-6,7-DI HYDROXY-1,2,3,4-TETRAHYDR OISOQUINOLINE 2463 Deoxycorticosterone MCMC00008282 DESOXYCORTONE 527 Anemonol MCMC00008516 PROTOANEMONIN 4039 Glucuronic acid MCMC00008637 GLUCURONIC ACID 3696 Galactitol MCMC00008677 ALEXITOL SODIUM 9795 Trigonelline MCMC00008746 CAFFEARINE 995 Benzyl isothio cyanate MCMC00008806 OLEUM TROPAEOLI 5220 Isopelletierine MCMC00008877 ISOPELLETIERINE

1819 Coniine MCMC00008886 CICUTINE 7572 Paeonol MCMC00008957 PEONOL 526 Anemonin MCMC00009027 ANEMONIN 9729 Triacanthine MCMC00009083 TRIACANTHINE 491 Anabasine MCMC00009092 ANABASINE NEONICOTINE 3856 Geraniol MCMC00009151 GERANIOL 7963 Plumbagin MCMC00009172 PLUMBAGIN 8703 Scoparone MCMC00009184 SCOPARONE 7661 Peganine MCMC00009197 PEGANINE 3824 Genipin MCMC00009224 GENIPIN 6182 Mescaline MCMC00009250 MESCALINE 729 Armillarisin A MCMC00009273 ARMILLARISIN A 642 Apiol MCMC00009307 APIOL 1899 Cotarnine MCMC00009319 COTARNINE 1155 Bufotenine MCMC00009324 BUFOTENINE 677 Arbutin MCMC00009331 ARBUTIN 8570 Salsolidine MCMC00009337 SALSOLIDINE 4330 Harmine MCMC00009392 BANISTERINE 2949 Dioscorine MCMC00009432 DIOSCORINE 5442 Kawain MCMC00009481 CAVAIN 1916 Coumestrol MCMC00009536 COUMESTROL 3578 Flavone MCMC00009538 FLAVONE 8237 Quercetin MCMC00009540 QUERCETIN 7917 Pinocembrin MCMC00009552 PINOCEMBRIN 7751 Peucedanin MCMC00009564 PEUCEDANIN 7488 Osthole MCMC00009573 OSTHOLE 255 Aesculin MCMC00009574 ESCULIN 4187 Guaiazulene MCMC00009577 GUAJAZULEN 323 Alantolactone MCMC00009588 ALANTCAMPHOR 9268 Tauremisin MCMC00009589 VULGARIN 7992 Polygodial MCMC00009597 POLYGODIAL 8598 alpha-Santalol MCMC00009603 SANTALOL 4469 Himachalol MCMC00009606 HIMACHALOL 1093 Bornyl isovalerianate MCMC00009609 BORNYVAL 29 Acacetin MCMC00009619 ACACETIN 1335 Capillarisin MCMC00009621 CAPILLARISIN 4954 Imperatorin MCMC00009632 PENTOSALEN 5869 Lycorine MCMC00009640 AMARYLLINE 3848 Gentiopicrin MCMC00009670 GENTIOPICRIN 5956 Magnolol MCMC00009776 MAGNOLOL 4527 Honokiol MCMC00009777 HONOKIOL 3137 Enterolactone MCMC00009779 ENTEROLACTONE 10426 Zearalenone MCMC00009793 ZEARALENONE 920 Bakuchiol MCMC00009801 BAKUCHIOL

8638 Sarracine MCMC00009817 SARRACINE 7952 Platyphylline MCMC00009818 PLATIFILLIN 7443 Oleic acid MCMC00009823 OLEIC ACID 856 Atranorin MCMC00009835 ATRANORIC ACID 1159 Bulbocapnine MCMC00009839 BULBOCAPNINE 1085 Boldine MCMC00009847 BOLDINE 2024 Cupreine MCMC00009850 CUPREIDINE 518 Androsterone MCMC00009879 ANDROSTERONE 1539 Chelidonine MCMC00009897 CHELIDONINE 1305 Canadine MCMC00009900 CANADINE 4580 Hydroquinine MCMC00009942 DIHYDROCHININ 4579 Hydroquinidine MCMC00009943 DIHYDROCHINIDIN 5 Abietic acid MCMC00009957 ABIETAL 508 Andrographolide MCMC00009960 ANDROGRAPHOLIDE 2040 Curcumin MCMC00009980 CURCUMIN 7579 Palmatine MCMC00009987 CALYSTIGINE 366 Allocryptopine MCMC00009988 ALPHA-ALLOCRYPTOPINE 8380 Rhaponticin MCMC00009993 PONTICIN 9520 Tetrahydropalmatine MCMC00009995 CASEANINE 10342 Xylopinine MCMC00009996 NORCORALYDINE 3962 Glaucine MCMC00009997 GLAUCINE 2963 Diospyrol MCMC00010046 DIOSPYROL 829 Aspidospermine MCMC00010071 ASPIDOSPERMINE 1740 Clupanodonic acid MCMC00010079 ACIDUM CLUPADONICUM 510 Andromedotoxin MCMC00010081 ACETYLANDROMEDOL 265 Agaricic acid MCMC00010083 AGARICIC ACID 8454 Rotenone MCMC00010088 DERRIN 7073 Narceine MCMC00010091 NARCEINE 2469 Deoxygomisin A MCMC00010094 SCHIZANDRIN B 6052 Margaspidin MCMC00010125 MARGASPIDIN 4333 Harpagoside MCMC00010126 HARPAGOSIDE 5029 Irisquinone MCMC00010136 IRISQUINONE A 2461 Deoxycholic acid MCMC00010137 ACIDUM DESOXYCHOLICUM 7445 Oleuropein MCMC00010143 OLEUROPEIN 1271 Calophyllolide MCMC00010152 CALOPHYLLOLIDE 287 Agrimophol MCMC00010159 AGRIMOPHOL 5400 Kaempferitrin MCMC00010168 KAEMPFERITRIN 7085 Naringin MCMC00010170 AURANTIIN 1773 Colchicoside MCMC00010173 COLCHICOSIDE 10214 Vitamin Edelta MCMC00010182 DELTA-TOCOPHEROL 4334 Harringtonine MCMC00010191 HARRINGTONINE 9111 Stigmasterol MCMC00010218 STIGMASTERIN 8903 beta-Sitosterol MCMC00010219 BETA-SITOSTERINUM 4161 Gossypol MCMC00010223 GOSSYPOL

9129 Strospeside MCMC00010233 STROSPESIDE 4086 Glycyrrhetic acid acetate MCMC00010246 ACETYLENOXOLONE ALUMINIUM 7432 Oleandrin MCMC00010247 NERIOLIN 8698 Scillaren A MCMC00010274 GLUCOPROSCILLARIDIN A 6657 Methyllycaconitine MCMC00010282 MELLICTINE 2404 Delsemine A MCMC00010283 DELSEMINE 3092 Elatine MCMC00010287 ELATINE 8790 Sennoside A MCMC00010296 SENNOSIDES A+B 787 Asiaticoside MCMC00010315 ASIATICOSIDE 9697 Tomatine MCMC00010323 LYCOPERSICIN 1006 Bergapten MCMC00010368 5-METHOXYPSORALEN 9947 Tryptanthrin MCMC00010381 COUROUPITINE A 7082 Naringenin MCMC00010385 NARINGENIN 9179 Swertiamarin MCMC00010390 SWERTIAMARIN 9449 Tenulin MCMC00010396 TENULIN 908 Baicalin MCMC00010411 BAICALIN 2064 Cyasterone MCMC00010427 CYASTERONE 402 Aloin MCMC00010449 ALOIN 10211 Vitamin D2 MCMC00010458 ERGOCALCIFEROL 4897 Hyoscine MCMC00010476 SCOPOLAMINE 719 Aristolochic acid MCMC00010486 ARISTOLOCHIC ACID 3113 Ellipticine MCMC00010489 ELLIPTICINE 3525 Farrerol MCMC00010493 FARREROL 646 Apoatropine MCMC00010499 APOATROPINE 575 Anisodamine MCMC00010502 ANISODAMINE 3504 Falcarindiol MCMC00010503 FALCARINDIOL 9755 Trichodermin MCMC00010505 TRICHODERMIN 3475 Eupatorin MCMC00010514 EUPATORIN 10051 Usnic acid MCMC00010515 USNIC ACID 9627 Theophylline MCMC00010547 AMINOPHYLLINE 1544 Chenodeoxycholic acid MCMC00010583 CHENODIOL 3946 Gitoxin MCMC00010701 GITOXIN 1904 Coumarin MCMC00010708 COUMARIN 906 Baicalein MCMC00010715 BAICALEIN 9507 DELTA-8-Tetrahydrocannabinol MCMC00010717 DELTA-8-TETRAHYDROCANN ABINOL 4987 Inositol c MCMC00010733 MYO-INOSITOL 3121 Emodin MCMC00010736 EMODIN 10024 Uracil MCMC00010738 URACIL 627 Apigenin MCMC00010749 APIGENIN 5721 Limonene MCMC00010774 LIMONENE 9352 Taxol MCMC00010874 PACLITAXEL 3352 alpha-Estradiol MCMC00010885 ALFATRADIOL

Table S2. TCMs justified by Western medicine. TCM Name/Species Source Activitya CMC agents CMC number/TCMD number)b Bai He/Lilium brownii var. Ben Jing1 Laxative Emodin viridulum MCMC00010736/3121)

Bai Yao Zi/Stephania Yao Xing Lun2 Antipyretic Berberine sulfate cepharantha MCMC00000967/1002) Bai Yao Zi/Stephania Yao Xing Lun2 Analgesic Codeine cepharantha MCMC00006992/1758) Morphine MCMC00006943/6921) Ban Xia/Pinellia ternata Ben Jing1 Analgesic Cicutine MCMC00008886/1819) Bei Ma Dou Ling Gen/ Yi Lin Zuan Yao3 Vulnerary Allantoin Aristolochia contorta(root) MCMC00000584/359) Bei Xuan Shen/ Yao Xing Lun2 Analgesic Harpagoside Scrophularia buergeriana MCMC00010126/4333) Bin Lang/Areca catechu Ming Yi Bie Lu4 Anthelmintic Arecoline MCMC00006149/691) Cha Ye/Camellia sinensis Shen Nong Shi Jing5 Diuretic Caffeine (leaf) MCMC00000179/1237) Theobromine MCMC00000463/9626) Chai Hu/ Yao Xing Lun2 Analgesic Eugenol Bupleurum chinense MCMC00000582/3437) Chan Chu/ Si Min Yue Ling6 Dermatologic Cinobufagin Bufo bufogargarizans; Bufo MCMC00008153/1662) melanostictus Chan Su/ Yi Xue Ru Men7 Dermatologic Cinobufagin Bufo bufo gargarizans; Bufo MCMC00008153/1662) melanostictus Chan Su/ Ben Cao Zheng8 Analgesic Morphine Bufo bufo gargarizans; Bufo MCMC00006943/6921) melanostictus Chao Xian Yin Yang Ben Jing1 Laxative Emodin Huo/Epimedium koreanum MCMC00010736/3121) Chou Cao/Ruta graveolens Sheng Cao Yao Xing Dermatologic 5-Methoxypsoralen Bei Yao9 MCMC00010368/1006) Chuan Huang Qin/ Ben Cao Zheng8 Antiasthmatic Baicalin Scutellaria hypericifolia MCMC00010411/908) Da Huang/Rheum officinale Ben Jing1 Laxative Emodin MCMC00010736/3121) Sennosides A+B MCMC00010296/8790) Da Suan/Allium sativum Shi Liao Ben Cao10 Anthelmintic Geraniol MCMC00009151/3856) Dang Gui/Angelica sinensis Ben Jing1 Dermatologic Azelaic acid MCMC00006166/891) Dang Gui/Angelica sinensis Yi Xue Qi Yuan11 Hematopoietic Cyanocobalamine

MCMC00006978/10209) Dian Huang Qin/Scutellaria Ben Cao Zheng8 Antiasthmatic Baicalin amoena MCMC00010411/908) Ding Xiang/ Yao Xing Lun2 Analgesic Eugenol Syzygium aromaticum MCMC00000582/3437) Dong Gua Zi/ Cui Yu Xi Shi Jing12 Diuretic Urea Benincasa hispida(seed) MCMC00000152/10032) Er Cha Gou Teng/Uncaria Ben Cao Gang Mu13 Astringent Gallic acid gambier MCMC00006710/3715) Fei Long Zhang Xue/ Fen Lei Cao Yao Analgesic Eugenol Toddalia asiatica Xing14 MCMC00000582/3437) Gan Di Huang/Rehmannia Ming Yi Bie Lu4 Diuretic Mannitol glutinosa MCMC00000331/6026) Gan Su Huang Qin/ Ben Cao Zheng8 Antiasthmatic Baicalin Scutellaria rehderiana MCMC00010411/908) Gao Liang Jiang/Alpinia Ming Yi Bie Lu4 Analgesic Eugenol officinarum MCMC00000582/3437) Ge Gen/Pueraria lobata Ri Hua Zi Ben Cao15 Vulnerary Allantoin (root) MCMC00000584/359) Gou Qi Zi/ Ben Cao Shu16 Hepatoprotective Taurine Lycium chinense(seed) MCMC00005803/9270) Gu Sui Bu/ Kai Bao Ben Cao17 Antihemorrhagic Aurantiin Drynaria fortunei MCMC00010170/7085) Guan Zhong/ Ben Cao Gang Mu13 Antihemorrhagic Aurantiin Dryopteris crassirhizoma MCMC00010170/7085) Guang Huo Xiang/ Ming Yi Bie Lu4 Analgesic Eugenol Pogostemon cablin MCMC00000582/3437) Gui Pi/Cinnamomum Ben Cao Shi Yi18 Analgesic Eugenol japonicum(cortex) MCMC00000582/3437) Hang Bai Zhi/Angelica Ri Hua Zi Ben Cao15 Dermatologic 5-Methoxypsoralen taiwaniana MCMC00010368/1006) He Shou Wu/Polygonum Ri Hua Zi Ben Cao15 Laxative Emodin multiflorum MCMC00010736/3121) He Zi/ Ben Cao Gang Mu13 Astringent Gallic acid Terminalia chebula(seed) MCMC00006710/3715) Hong Se Jin Ji Na Gang Mu Shi Yi19 Antimalarial Quinine Shu/Cinchona succirubra MCMC00006534/8284) Hu Zhang/ Yao Xing Lun2 Laxative Emodin Polygonum cuspidatum MCMC00010736/3121) Hu Zhang/ Ben Cao Shi Yi18 Antihemorrhagic Quercetin Polygonum cuspidatum MCMC00009540/8237) Huang Bai/ Ben Jing1 Antipyretic Berberine sulfate Phellodendron amurense MCMC00000967/1002) Huang Hao/ Ming Yi Bie Lu4 Dermatologic Azelaic acid

Artemisia scoparia MCMC00006166/891) Huang Hao/ Ben Jing1 Laxative Emodin Artemisia scoparia MCMC00010736/3121) Huang Hao/ Yu Qiu Yao Jie20 Analgesic Eugenol Artemisia scoparia MCMC00000582/3437) Huang Hao/ Ming Yi Bie Lu4 Dermatologic Salicylic acid Artemisia scoparia MCMC00000332/8564) Huang Hua Hao/ Tang Ben Cao21 Antihemorrhagic Quercetin Artemisia annua MCMC00009540/8237) Huang Hua Hao/ Ben Jing1 Dermatologic Salicylic acid Artemisia annua MCMC00000332/8564) Huang Hua Hao/ Ben Jing1 Anthelmintic Santonin Artemisia annua MCMC00007922/8606) Huang Lian/ Ben Jing1 Antipyretic Berberine sulfate Coptis chinensis MCMC00000967/1002) Huang Qi/ Ri Hua Zi Ben Cao15 Detoxicant Glucuronic acid Astragalus membranaceus MCMC00008637/4039) Ji Zi Bai/Gallus gallus Ming Yi Bie Lu4 Analgesic Aminobenzoic acid domesticus MCMC00000880/429) Jian Zi Su Ye/Perilla Dian Nan Ben Cao22 Analgesic Eugenol frutescens var. acuta (leaf) MCMC00000582/3437) Jin Ji Le/ Gang Mu Shi Yi19 Antimalarial Cinchonidine Cinchona ledgeriana MCMC00007810/1632) Cinchonine MCMC00007013/1633) Dihydrochinin MCMC00009942/4580) Quinine MCMC00006534/8284) Jiu Li Xiang/ Sheng Cao Yao Xing Analgesic Eugenol Murraya paniculata Bei Yao9 MCMC00000582/3437) Jue Ming Zi/ Ben Jing1 Laxative Emodin Cassia tora(seed) MCMC00010736/3121) Ku Tan Zi/ Cao Mu Bian Fang23 Insecticide Derrin Millettia pachycarpa(seed) MCMC00010088/8454) Ku Tan Zi/ Cao Mu Bian Fang23 Dermatologic Derrin Millettia pachycarpa(seed) MCMC00010088/8454) Kuan Ye Xiang Pu/ Ben Jing1 Antihemorrhagic Quercetin Typha latifolia MCMC00009540/8237) Lang Dang Zi/ Ming Yi Bie Lu4 Antispasmodic Atropine Hyoscyamus niger(seed) MCMC00006515/857) Scopolamine MCMC00010476/4897)

Apoatropine MCMC00010499/646) Liu Bai Pi/ Tang Ben Cao21 Analgesic Salicin Salix babylonica(tegument) MCMC00007023/8562) Liu Zhi/ Tang Ben Cao21 Analgesic Salicin Salix babylonica(twig) MCMC00007023/8562) Long Dan/Gentiana scabra Yi Xue Qi Yuan11 Analgesic Swertiamarin MCMC00010390/9179) Long Ya Cao/Agrimonia Gang Mu Shi Yi19 Anthelmintic Agrimophol pilosa MCMC00010159/287) Lu Hui/Aloe vera Kai Bao Ben Cao17 Detoxicant Glucuronic acid MCMC00008637/4039) Luo Le/Ocimum basilicum Ming Yi Bie Lu4 Analgesic Eugenol MCMC00000582/3437) Ma Liu Ye/Pterocarya Fen Lei Cao Yao Dermatologic Salicylic acid stenoptera(leaf) Xing14 MCMC00000332/8564) Mei Gui Hua/ Ben Cao Zai Xin24 Analgesic Eugenol Rosa rugosa(flower) MCMC00000582/3437) Mo Shi Zi/ Yao Xing Lun2 Astringent Gallic acid Quercus infectoria MCMC00006710/3715) Mo Yao/ Yao Xing Lun2 Analgesic Eugenol Commiphora myrrha MCMC00000582/3437) Mo Yao/ Ri Hua Zi Ben Cao15 Antiseptic Metacresol Commiphora myrrha MCMC00007632/1926) Mu Hu Die/ Dian Nan Ben Cao22 Antiasthmatic Baicalin Oroxylum indicum MCMC00010411/908) Mu Jin Pi/Hibiscus Ben Cao Gang Mu13 Dermatologic Azelaic acid syriacus(tegument) MCMC00006166/891) Mu Xu/Medicago sativa Shi Liao Ben Cao10 Hepatoprotective Caffearine MCMC00008746/9795) Mu Zei/Equisetum hiemale Ben Cao Gang Mu13 Antihemorrhagic Quercetin MCMC00009540/8237) Ni Bo Er Yang Ti/ Dian Nan Ben Cao22 Laxative Emodin Rumex nepalensis MCMC00010736/3121) Nian Mao Huang Qin/ Ben Cao Zheng8 Antiasthmatic Baicalin Scutellaria viscidula MCMC00010411/908) Niu Xue/Bos taurus Yi Lin Zuan Yao3 Diuretic Urea domesticus; Bubalus bubalis MCMC00000152/10032) Pu Huang/Typha angustata Ben Jing1 Diuretic Mannitol MCMC00000331/6026) Pu Huang/Typha angustata Ben Jing1 Antihemorrhagic Quercetin MCMC00009540/8237) Pu Tao/Vitis vinifera Yi Lin Zuan Yao3 Astringent Gallic acid MCMC00006710/3715)

Qing Jiao/ Ben Jing1 Dermatologic 5-Methoxypsoralen Zanthoxylum schinifolium MCMC00010368/1006) Qing Mu Xiang/ Yi Lin Zuan Yao3 Vulnerary Allantoin Aristolochia debilis MCMC00000584/359) Qu Mai/Dianthus superbus Ri Hua Zi Ben Cao15 Pediculicide Benzyl benzoate MCMC00000701/990) Ren Shen/Panax ginseng Zhen Zhu Nang25 Hematopoietic Cyanocobalamine MCMC00006978/10209) Ri Ben Xiao Bo/Berberis Tang Ben Cao21 Antipyretic Berberine sulfate thunbergii MCMC00000967/1002) San Qi/ Ben Cao Gang Mu13 Antihemorrhagic Quercetin Panax pseudo-ginseng var. MCMC00009540/8237) notoginseng Sang Ye/Morus alba(leaf) Ri Hua Zi Ben Cao15 Hepatoprotective Caffearine MCMC00008746/9795) Sang Ye/Morus alba(leaf) Ben Cao Shi Yi18 Analgesic Eugenol MCMC00000582/3437) Shan Zhu Yu/ Ben Cao Zheng8 Astringent Gallic acid Cornus officinalis MCMC00006710/3715) She Xiang/ Yao Xing Lun2 Vulnerary Allantoin Moschus moschiferus; MCMC00000584/359) Moschus berezovskii; Moschus sifanicus Shi Liu Gen/Punica Ming Yi Bie Lu4 Anthelmintic Isopelletierine granatum(root) MCMC00008877/5220) Shi Suan/Lycoris radiata Ben Cao Gang Mu13 Emetic Amarylline MCMC00009640/5869) Shi Zhu/Dianthus chinensis Ri Hua Zi Ben Cao15 Analgesic Eugenol MCMC00000582/3437) Shu Li/Rhamnus davurica Shi Liao Ben Cao10 Laxative Emodin MCMC00010736/3121) Shu Zhang Lao Guan Dian Nan Ben Cao22 Hemostatic Ellagic acid Cao/Geranium sibiricum MCMC00001113/3112) Shui Yang Mu Bai Pi/Salix Ben Cao Gang Mu13 Analgesic Salicin purp Urea (tegument) MCMC00007023/8562) Tang Gu Te Da Huang/ Ben Jing1 Laxative Emodin Rheum tanguticum MCMC00010736/3121) Sennosides A + B MCMC00010296/8790) Tu Huang Lian/Berberis Dian Nan Ben Cao22 Antipyretic Berberine sulfate julianae MCMC00000967/1002) Wu Hua Guo/Ficus carica Dian Nan Ben Cao22 Dermatologic 5-Methoxypsoralen MCMC00010368/1006) Xi Xin/Asarum sieboldii Ben Jing1 Analgesic Eugenol

MCMC00000582/3437) Xia Ye Xiang Pu/ Ben Jing1 Antihemorrhagic Quercetin Typha angustifolia MCMC00009540/8237) Xian He Cao Gen Ya/ Ben Jing1 Anthelmintic Agrimophol Agrimonia pilosa var. MCMC00010159/287) japonica (root and bud) Xian He Cao/ Agrimonia Bao Qing Ben Cao Hemostatic Ellagic acid pilosa var. japonica Zhe Zhong26 MCMC00001113/3112) Xian He Cao/ Agrimonia Bao Qing Ben Cao Antihemorrhagic Quercetin pilosa var. japonica Zhe Zhong26 MCMC00009540/8237) Xiang Zhang/Cinnamomum Ben Cao Shi Yi18 Analgesic Eugenol parthenoxylum MCMC00000582/3437) Xiao Cao Wu/Delphinium Dian Nan Ben Cao22 Analgesic Eugenol yunnanense MCMC00000582/3437) Xiao Mai/Triticum aestivum Ben Cao Gang Mu13 Vulnerary Allantoin MCMC00000584/359) Xin Yi/Magnolia liliflora Ben Jing1 Analgesic Eugenol MCMC00000582/3437) Ya Pian/ Ben Cao Qiu Yuan27 Analgesic Codeine Papaver somniferum MCMC00006992/1758) Narceine MCMC00010091/7073) Thebaine MCMC00007012/9620) Yan Fu Zi/Rhus chinensis Ben Cao Gang Mu13 Astringent Gallic acid MCMC00006710/3715) Yang Ti/Rumex japonicus Dian Nan Ben Cao22 Laxative Emodin MCMC00010736/3121) Yin Chen Hao/Artemisia Ben Cao Jing Ji Zhu28 Analgesic Eugenol capillaris MCMC00000582/3437) Ying Su Ke/Papaver Dian Nan Ben Cao22 Antitussive Noscapine somniferum(tegument) MCMC00007018/7074) Codeine MCMC00006992/1758) Ying Su Ke/Papaver Dian Nan Ben CaoTu Analgesic Codeine somniferum(tegument) Shuo29 MCMC00006992/1758) Thebaine MCMC00007012/9620) Zhang Mu/Cinnamomum Ben Cao Shi Yi18 Analgesic Eugenol camphora MCMC00000582/3437) Zhang Ye Da Huang/ Ben Jing1 Laxative Danthron Rheum palmatum MCMC00000683/1583) Emodin MCMC00010736/3121)

Sennosides A+B MCMC00010296/8790) Zhe Gu Cai/ Caloglossa Gang Mu Shi Yi19 Parasiticide Kainic acid leprieurii MCMC00007056/5422) Zhe Gu Cai/ Caloglossa Gang Mu Shi Yi19 Anthelmintic Kainic acid leprieurii MCMC00007056/5422) Zi Yu Lan Hua/ Ben Jing1 Analgesic Eugenol Magnolia liliflora(flower) MCMC00000582/3437) 1 Anonymous, Eastern Han Dynasty (25 AD ~ 220 AD) 2 Zhen Quan, 541 AD ~ 643 AD 3 Wang Fu, 1758 AD 4 Tao Hong-Jing, Liang Dynasty (502 AD ~ 536 AD) 5 Anonymous, Eastern Han Dynasty (25 AD ~ 220 AD) 6 Cui Shi, 130 AD ~ 180 AD 7 Li Chan, 1575 AD 8 Zhang Jing-Yue, 1640 AD 9 He Ke-Jian, 1711 AD 10 Meng Shen, 713 AD ~ 739 AD 11 Zhang Yuan-Su, 1131 AD ~ 1234 AD 12 Cui Yu-Xi, 730 AD ~ 780 AD 13 Li Shi-Zhen, 1596 AD 14 Anonymous, Qing Dynasty (1644 AD ~ 1911 AD) 15 Anonymous, 908 AD ~ 912 AD 16 Liu Ruo-Jin, 1628 AD ~ 1644 AD 17 Liu Han, 973 AD 18 Chen Zang-Qi, 741 AD 19 Zhao Xue-Min, 1765 AD 20 Huang Yuan-Yu, 1754 AD 21 Li Ji, 657 AD ~ 659 AD 22 Lan Mao, 1436 AD 23 Liu Shan-Shu, 1871 AD 24 Ye Gui, 1757 AD ~ 1790 AD 25 Zhang Yuan-Su, 1131 AD ~ 1234 AD 26 Chen Yan, 1248 AD 27 Zhao Qi-Guang, 1848 AD 28 Tao Hong-Jing, Liang Dynasty (502 AD ~ 536 AD) 29 Fan Hong, 1556 AD a recorded in the corresponding Chinese medicinal books b CMC agents contained in the TCM, which show the same activity as the TCM

Table S3. Components of Coptidis rhizome. TCMD ID Key Name 1002 Berberine 1370 3-Carboxy-4-hydroxy-phenoxy glucoside

1787 Columbamine 1836 Coptisine 2813 3,4-Dihydroxyphenylethyl alcohol glucoside 3550 Ferulic acid 5336 Jatrorrhizine 5942 Magnoflorine 7380 Obaculactone 7382 Obacunone 7579 Palmatine 9802 2,3,4-Trihydroxy-benzenepropanoic acid

Table S4. Components of Evodia rutaecarpa. TCMD ID Key Name 79 6alpha-Acetoxy-5-epilimonin 80 6beta-Acetoxy-5-epilimonin

662 Arachidoside 2820 Dihydroxyrutaecarpine 2887 3-Dimethylallyl-4-methoxy-2-quinolone 2912 N,N-Dimethyl-5-methoxy tryptamine 3492 Evocarpine 3493 Evodiamide 3494 Evodiamine 3495 Evodinone 3496 Evodol 3594 14-Fomyldihydroxyrutaecarpine 4152 Goshuynic acid 4153 Goshuyuamide I 4154 GoshuyuamideII 4169 Graucin A 4692 Hydroxyevodiamine 4693 12alpha-Hydroxyevodol 4737 12alpha-Hydroxylimonine 5721 Limonene 6369 N-(2-Methylaminobenzoyl)tryptamine 6373 N-Methylanthranylamide 6510 1-Methyl-2-dodecyl-4-(1H)- quinolone 6511 1-Methyl-2-dodecyl-4-(1H)-quinolone 6694 1-Methyl-2-nonyl-4(1H)-quinolone 6714 1-Methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone 6717 1-Methyl-2-[(Z)-6-pentadecenyl]-4(1H)-quinolone 6718 1-Methyl-2-[(Z)-10-pentadecenyl]-4-(1H)-quinolone 6719 1-Methyl-2-pentadecyl-4(1H)-quinolone 6720 1-Methyl-2-[(Z)-9-pentadecenyl]-4-(1H)-quinolone 6768 1-Methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone 6795 1-Methyl-2-[(4Z,7Z)-4,7-tridecadienyl]-4(1H)-quinolone 6796 1-Methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone 6812 1-Methyl-2-[(Z)-5-undecenyl]-4-(1H)- quinolone 6813 1-Methyl-2-[(Z)-6-undecenyl]-4(1H)-quinolone 6814 1-Methyl-2-undecyl-4(1H)-quinolone 7380 Obaculactone 7382 Obacunone 7389 Ocimene 8497 Rutaecarpine 8498 Rutaevine 8499 Rutaevine acetate 9188 Synephrine 9517 1,2,3,4-Tetrahydrol-oxo-beta-carboline 9783 2-Tridecyl-4-(1H)-quinolone