Supporting Information
Table S1 Structure and biological activity of internal dataset compounds
A
Cpda,b / Scaffold / R1 / R2 / R3 / IC50(mM)1(Ts44) / A / CH3 / OSO2C6H4CH3-p / OCH3 / 30.4
2(P13) / A / CH=CHC6H3(OCH3)2-3',4'(E) / OSO2CH3 / OCH3 / 46.6
3(Ts99) / A / CH3 / N3 / OCH3 / 73.7
4(Ts96) / A / CH=CHC6H3(OCH3)2-3',4'(E) / N3 / OCH3 / 71.3
5(Ts34) / A / CH3 / NH2 / OCH3 / 24.1
6(Ts95) / A / CH=CHC6H3(OCH3)2-3',4'(E) / NH2 / OCH3 / 70.6
7(Ts93) / A / CH2CH2C6H3(OCH3)2-3', 4' / NH2 / OCH3 / 68.4
8(Ts122) / A / CH3 / NHCOC6H5 / OCH3 / 122.5
9(Ts121) / A / CH3 / NHCOC6H4Cl-p / OCH3 / 121.7
10(Ts113) / A / CH3 / NHCOC6H2(OCH3)3-3',4',5' / OCH3 / 98.4
11(Ts103) / A / CH3 / NHCOC5H4N-3' / OCH3 / 78.4
12(Ts107) / A / CH3 / NHCOC4H3N2-2',5' / OCH3 / 82.6
13(P23) / A / CH=CHC6H3(OCH3)2-3',4'(E) / NHCOC5H4N-3' / OCH3 / 137.3
14(Ts136) / A / ÇH2CH2C6H3(OCH3)2-3',4' / NHCOCH=CHC6H5(E) / OCH3 / 232.7
15(Ts48) / A / CH3 / NHCOC6H2(OCH3)3-3',4',5' / NHOH / 33.5
16(Ts40) / A / CH3 / NHCOC5H4N-3' / NHOH / 29.8
17(Ts76) / A / CH3 / NHCOCH=CHC6H5(E) / NHOH / 56.1
18(Ts85) / A / ÇH2CH2C6H3(OCH3)2-3',4' / NHCOC5H4N-3' / NHOH / 62.2
19(Ts120) / A / CH3 / NHCOC6H2(OCH3)3-3',4',5' / NHCH2COOCH3 / 121.5
B
Cpda,b / Scaffold / R1 / R2 / R3 / R4 / IC50(mM)20(P11) / B / p-CH3C6H4 / OCH3 / OH / H / 38.4
21(Ts74) / B / C6H5 / OCH3 / OH / H / 53.8
22(Ts63) / B / CH3 / OCH3 / OH / H / 41.6
23(Ts75) / B / p-CH3C6H4 / OCH3 / C=O / 54.9
24(Ts102) / B / C6H5 / OCH3 / C=O / 75.8
25(Ts127) / B / p-CH3C6H4 / OCH3 / O-(CH2)2-O / 155.8
26(Ts123) / B / p-CH3C6H4 / OCH3 / O-(CH2)4-O / 124.3
27(Ts126) / B / C6H5 / OCH3 / O-(CH2)2-O / 150.6
28(Ts128) / B / C6H5 / OCH3 / O-(CH2)3-O / 168.1
29(Ts125) / B / C6H5 / OCH3 / O-(CH2)4-O / 134.8
30(Ts70) / B / p-CH3C6H4 / NHOH / O-(CH2)2-O / 48.5
31(P16) / B / p-CH3C6H4 / NHOH / O-(CH2)3-O / 61.8
32(Ts98) / B / p-CH3C6H4 / NHOH / O-(CH2)4-O / 73.2
33(Ts80) / B / C6H5 / NHOH / O-(CH2)2-O / 57.8
34(Ts108) / B / C6H5 / NHOH / O-(CH2)3-O / 82.7
C
Cpda,b / Scaffold / R1 / R2 / IC50 (mM)35(Ts33) / C / H / OC2H5 / 23.7
36(Ts87) / C / CH3 / OC2H5 / 64.3
37(Ts38) / C / CH(CH3)2 / OC2H5 / 28.8
38(Ts46) / C / CH2CH(CH3)2 / OC2H5 / 30.8
39(Ts30) / C / CH(CH3)CH2CH3 / OC2H5 / 23.3
40(Ts55) / C / CH2C6H5 / 38.1
41(Ts25) / C / / OC2H5 / 18.9
42(Ts65) / C / (CH2)2CH3 / OC2H5 / 42
43(Ts26) / C / / OC2H5 / 20.7
44(Ts23) / C / 4(OH)C6H4CH2 / OC2H5 / 16.9
45(Ts62) / C / (CH2)4NH2 / OC2H5 / 41
46(Ts47) / C / / OC2H5 / 32.1
47(P6) / C / H / OH / 15.4
48(Ts21) / C / CH(CH3)2 / OH / 15.8
49(Ts28) / C / CH2CH(CH3)2 / OH / 22.1
50(Ts22) / C / CH(CH3)CH2CH3 / OH / 16.6
51(Ts24) / C / CH2C6H5 / OH / 16.9
52(Ts20) / C / (CH2)4NH2 / OH / 14.1
53(Ts17) / C / / OH / 13.2
54(Ts13) / C / 4(OH)C6H4CH2 / NHOH / 11.3
55(Ts8) / C / H / NHOH / 9.4
56(Ts12) / C / CH3 / NHOH / 10.9
57(Ts16) / C / CH(CH3)2 / NHOH / 12.5
58(Ts6) / C / CH(CH3)CH2CH3 / NHOH / 92
59(P1) / C / CH2C6H5 / NHOH / 1.8
60(Ts7) / C / (CH2)4NH2 / NHOH / 9.4
61(Ts10) / C / / NHOH / 9.7
62(Ts5) / C / 4-(OH)C6H4CH2 / NHOH / 7.3
D
Cpda,b / Scaffold / R1 / R2 / IC50 (mM)63(Ts15) / D / NO2 / L-Cys-NH2 / 12.4
64(Ts9) / D / NO2 / D-Phe-L-Leu-NH2 / 9.4
65(Ts3) / D / NO2 / D-Phe-L-isoSer-NH2 / 6.5
66(Ts86) / D / NH2 / L-Leu-NH2 / 63.2
67(P3) / D / NH2 / D-Phe-L-Leu-NH2 / 6.1
68(Ts45) / D / I / L-Leu-NH2 / 30.6
69(Ts14) / D / I / D-Phe-L-Leu-NH2 / 11.3
E
Cpda,b / Scaffold / R / IC50 (mM)70(Ts1) / E / / 5
71(Ts4) / E / / 6.92
72(P18) / E / / 74
73(Ts73) / E / / 53.43
74(Ts19) / E / Gly-OCH2Ph / 13.45
75(Ts112) / E / L-Ala-OCH2Ph / 91.61
76(Ts41) / E / L-Val-OCH2Ph / 301.40
77(Ts42) / E / L-Leu-OCH2Ph / 301.70
78(Ts2) / E / L-Phe-OCH2Ph / 6.48
79(Ts57) / E / Gly-OH / 38.74
80(Ts18) / E / L-Val-OH / 13.33
81(P4) / E / L-Leu-OH / 8.42
82(Ts92) / E / L-Phe-OH / 66.4
F
Cpda,b / Scaffold / R1 / R2 / IC50 (mM)83(P25) / F / OH / nC3H7 / 9108.6
84(Ts150) / F / OH / iC3H7 / 2199.7
85(Ts131) / F / OH / nC5H11 / 204.3
86(Ts143) / F / OH / nC6H13 / 387.8
87(Ts134) / F / OH / nC8H17 / 232.2
88(Ts141) / F / OH / p-ClC6H4 / 348.5
89(Ts138) / F / OH / o-ClC6H4 / 263.4
90(Ts147) / F / OH / m-ClC6H4 / 718.6
91(Ts135) / F / OH / C6H5 / 232.4
92(Ts149) / F / OH / m-NO2C6H4 / 1781
93(Ts139) / F / OH / p-NO2C6H4 / 273.1
94(Ts148) / F / OH / 1-C10H7 / 739.2
95(Ts51) / F / NHOH / nC3H7 / 36
96(Ts91) / F / NHOH / iC3H7 / 65.9
97(P5) / F / NHOH / nC4H9 / 11.1
98(P20) / F / NHOH / o-ClC6H4 / 86.6
99(Ts88) / F / NHOH / C6H5CH2 / 65.1
100(Ts119) / F / NHOH / C6H5 / 115
G
Cpda,b / Scaffold / R1 / R2 / IC50(mM)101(P8) / G / p-CH3C6H4 / OH / 20.7
102(Ts31) / G / p-FC6H4 / OH / 23.4
103 (Ts50) / G / pClC6H5 / OH / 34.5
104(Ts81) / G / p-BrC6H4 / OH / 58.1
105(P21) / G / di-m-FC6H3 / OH / 98.6
106(Ts78) / G / o-FC6H4 / OH / 56.8
107(Ts56) / G / o-ClC6H4 / OH / 38.3
108(P19) / G / m-ClC6H4 / OH / 80.5
109(Ts124) / G / CH3 / OH / 125.8
110(Ts130) / G / C2H5 / OH / 184.3
111(Ts137) / G / C3H7 / OH / 237.5
112(Ts132) / G / i-C4H9 / OH / 207.2
113(Ts71) / G / CH2COOCH3 / OH / 50.4
114(P15) / G / CH(CH3)COOCH3 / OH / 55.1
115 (Ts83) / G / / OH / 60.5
116(P12) / G / / OH / 43.7
117(Ts140) / G / p-CH3C6H4 / NHC6H4CH3-P / 334.7
118(Ts142) / G / p-FC6H4 / NHC6H4F-P / 371.3
119(Ts144) / G / p-ClC6H4 / NHC6H4Cl-P / 405.2
120(Ts145) / G / o-FC6H4 / NHC6H4F-o / 405.2
121(Ts133) / G / / / 213.2
H
Cpda,b / Scaffold / R / IC50(mM)122(P10) / H / H / 33.2
123(Ts82) / H / CH3 / 59.3
124(Ts117) / H / C2H5 / 108.2
125(Ts146) / H / CH3CH2CH2 / 470.2
126(Ts118) / H / C6H5CH2 / 110.2
127(Ts90) / H / p-F-C6H4CH2 / 65.8
128(Ts105) / H / P-Cl-C6H4CH2 / 79.2
129(Ts110) / H / P-Br-C6H4CH2 / 88.7
130(Ts67) / H / P-OH-C6H4CH2 / 45.5
131(Ts53) / H / HOCH2 / 36.8
132(Ts72) / H / CH3SCH2CH2 / 50.7
133(Ts54) / H / C6H5SCH2CH2 / 37.8
134(Ts101) / H / Cbz-NHCH2CH2CH2 / 74.7
135(Ts77) / H / / 56.6
136(Ts39) / H / / 29.7
Cpda,b / Scaffold / IC50(mM)
137(Ts43) / - / / 30.2
138(Ts11) / - / / 10.2
139(P7) / - / / 18.5
140(Ts116) / - / / 107.6
141(Ts29) / - / / 22.8
I
Cpda,b / Scaffold / R / IC50(mM)142(Ts60) / I / / 40.1
143(Ts115) / I / 102.6
144(Ts109) / I / 87.7
145(Ts97) / I / / 72.4
146(Ts35) / I / / 24.3
147(Ts59) / I / / 40
148(Ts64) / I / / 41.9
149(Ts32) / I / / 23.4
150(Ts89) / I / / 65.8
151(Ts79) / I / / 57.8
152(Ts111) / I / / 89.6
153(Ts106) / I / / 80.4
154(Ts104) / I / 78.5
155(P17) / I / / 65.9
156(Ts68) / I / / 45.6
157(P14) / I / / 51.2
158 (P24) / I / / 805.1
J
Cpda,b / Scaffold / R1 / R2 / R3 / IC50 (mM)159 (P9) / J / pCH3C6H4 / C6H5CO / OCH3 / 24.8
160(Ts114) / J / pCH3C6H4 / P-CH3C6H4SO2 / OCH3 / 101.4
161(Ts100) / J / pCH3C6H4 / C6H5SO2 / OCH3 / 74.6
162(Ts62) / J / pCH3C6H4 / CH3SO2 / OCH3 / 41.4
163(Ts129) / J / pCH3C6H4 / (E)C6H5CH=CHCO / OCH3 / 168.6
164(Ts66) / J / C6H5 / C6H5CO / OCH3 / 43.8
165(Ts52) / J / C6H5 / P-ClC6H4CO / OCH3 / 36.4
166(Ts84) / J / C6H5 / P-CH3C6H4SO2 / OCH3 / 61.3
167(Ts69) / J / C6H5 / C6H5SO2 / OCH3 / 47.3
168(Ts58) / J / C6H5 / CH3SO2 / OCH3 / 39.5
169(Ts95) / J / CH3 / P-CH3C6H4SO2 / OCH3 / 68.9
170(Ts37) / J / CH3 / CH3SO2 / OCH3 / 28.4
171(P22) / J / CH3 / (E)C6H5CH=CHCO / OCH3 / 114.3
172(Ts27) / J / pCH3C6H4 / H / NHOH / 21.7
173(Ts49) / J / C6H5 / H / NHOH / 33.5
174(Ts36) / J / CH3 / H / NHOH / 26.3
aCpd = Compound number
b The 175th Compound is bestatin (P2)[6], see the main text for structure and activity
Table S2 Binding database compounds used as external dataset
Binding Database Display Namea / Ki (nM) / IC50 (nM) / Ref. Nob / APN sourcec / Substrate of APNcCHEBI:128922 / n/a / 0.011 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128909 / n/a / 0.020 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128921 / n/a / 0.020 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128910 / n/a / 0.021 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128865 / n/a / 0.022 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128981 / n/a / 0.025 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEMBL328470 / n/a / 0.028 / [2] / Porcine Kidney / L-Leu-p-nitroanilide
CHEBI:128984 / n/a / 0.030 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEMBL414393 / n/a / 0.030 / [3] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128847 / n/a / 0.040 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128967 / n/a / 0.045 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128983 / n/a / 0.045 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128934 / n/a / 0.056 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128933 / n/a / 0.090 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEBI:128932 / n/a / 0.130 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEMBL226864 / n/a / 0.240 / [4] / Not Mentioned / Not Mentioned
CHEMBL226911 / n/a / 0.500 / [4] / Not Mentioned / Not Mentioned
CHEMBL227345 / n/a / 0.530 / [4] / Not Mentioned / Not Mentioned
CHEMBL226863 / n/a / 0.550 / [4] / Not Mentioned / Not Mentioned
CHEMBL227290 / n/a / 0.600 / [4] / Not Mentioned / Not Mentioned
CHEMBL227340 / n/a / 0.710 / [4] / Not Mentioned / Not Mentioned
CHEMBL390323 / n/a / 0.830 / [4] / Not Mentioned / Not Mentioned
CHEMBL227347 / n/a / 0.930 / [4] / Not Mentioned / Not Mentioned
CHEMBL226912 / n/a / 1.000 / [4] / Not Mentioned / Not Mentioned
CHEMBL27693 / n/a / 1.100 / [5] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL91474 / n/a / 1.345 / [2] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL430903 / n/a / 1.628 / [2] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL1099248 / n/a / 1.800 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL288458 / n/a / 2.400 / [21] / Porcine Kidney / L-Leucine-2-Naphthylamide
Bestatin / n/a / 2.400 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL16471 / n/a / 2.700 / [2] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL35092 / n/a / 2.900 / [21] / Porcine Kidney / L-Leucine-2-Naphthylamide
CHEMBL387949 / n/a / 3.000 / [4] / Not Mentioned / Not Mentioned
CHEBI:322329 / n/a / 3.030 / [5] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL246122 / n/a / 3.100 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL182879 / n/a / 3.400 / [7] / Porcine Kidney / Ala-7-amido-4coumarine
CHEMBL37281 / n/a / 3.400 / [21] / Porcine Kidney / L-Leucine-2-Naphthylamide
Bestatin / n/a / 3.500 / [8] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL35627 / n/a / 3.800 / [21] / Porcine Kidney / L-Leucine-2-Naphthylamide
Bestatin / n/a / 3.900 / [7] / Porcine Kidney / Ala-7-amido-4coumarine
CHEMBL227289 / n/a / 4.000 / [4] / Not Mentioned / Not Mentioned
CHEBI:128876 / n/a / 4.000 / [1] / Hog Kidney / [3H] Leu-enkephalin
CHEMBL36081 / n/a / 5.000 / [21] / Porcine Kidney / L-Leucine-2-Naphthylamide
CHEMBL1098910 / n/a / 5.300 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL354438 / n/a / 7.000 / [11] / Porcine Kidney / L-Leucine-β-Naphthylamide
CHEMBL1095254 / n/a / 7.300 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL1099247 / n/a / 9.200 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL1097214 / n/a / 9.400 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL1095252 / n/a / 9.400 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL1095253 / n/a / 9.700 / [6] / Porcine Kidney / L-Leu-p-nitroanilide
CHEMBL368811 / n/a / 10.200 / [11] / Porcine Kidney / L-Leucine-β-Naphthylamide