Quantitative Structure-Activity Relationship Analysisof β-Amyloid Aggregation Inhibitors

Shiri Stempler1, Michal Levy-Sakin1, Anat Frydman-Marom1, Yaniv Amir1, Roni Scherzer-Attali1, Ludmila Buzhansky1, Ehud Gazit1 and Hanoch Senderowitz2*

Supporting Information

Content of SI

Table S1 (Training set molecules) ...... 2

Table S2 (Test set molecules)...... 4

Table S3 (List of descriptors calculated) ...... 5

TableS4(Compound attributes in training set) ...... 6

Table S5 (WEKA-J48 parameters)...... 6

Table S6 (Descriptorscorrelation matrix) ...... 7

Figure S1 (Molecular structures of compounds tested experimentally)...... 7

Table S1. Training set molecules

Name / Observed activity / Bayesian model / Decision tree model
acid red 27[1] / 0 / 0 / 0
acid red 731 / 0 / 0 / 0
acid violet 51 / 0 / 0 / 0
acid yellow 381 / 0 / 0 / 0
Aib-D-Phe-D-Phe[2] / 0 / 0 / 0
Aib-Tyr-Tyr2 / 0 / 0 / 0
apocodeine[3] / 0 / 0 / 0
carvedilol[4] / 1 / 1 / 1
curcumin[5] / 1 / 1 / 1
D0273 / 1 / 1 / 1
D0293 / 1 / 1 / 1
D0403 / 1 / 1 / 1
daunomycin[6] / 1 / 1 / 1
diacetoxy phenol red [7] / 0 / 0 / 0
doxorubicinone6 / 0 / 0 / 0
doxycyline6 / 0 / 0 / 0
ellagic acid7 / 0 / 1 / 1
epicatechin[8] / 1 / 1 / 1
exifone[9] / 1 / 1 / 1
ferulic acid [10] / 0 / 1 / 0
gossypetin9 / 1 / 1 / 1
kaempferol8 / 1 / 1 / 1
M1213 / 0 / 0 / 0
meclocycline6 / 0 / 0 / 0
minocycline6 / 0 / 0 / 0
morin8 / 1 / 1 / 1
myricetin8 / 1 / 1 / 1
nordihydroguauaretic acid8 / 1 / 1 / 0
oxytetracycline6 / 0 / 0 / 0
penimepicycline6 / 0 / 0 / 0
Phe-D-Pro2 / 0 / 0 / 0
Pro-Tyr-Tyr2 / 0 / 0 / 0
propyl gallate7 / 0 / 1 / 1
pseudohypericin9 / 1 / 1 / 1
purpurogallin9 / 1 / 0 / 1
pyridine[11] / 0 / 0 / 0
pyrocatechol7 / 0 / 0 / 1
RS-0466[12] / 0 / 1 / 1
Cl-NQTrp18 [13] / 0 / 0 / 0
reactive black 51 / 0 / 0 / 0
reactive blue1 / 0 / 0 / 0
rosmarinic acid [14] / 1 / 1 / 1
SKF-730334 / 0 / 0 / 0
SKF-817334 / 0 / 0 / 0
styryl benzene10 / 0 / 1 / 1
Cl-NQTrp13[15] / 1 / 1 / 1
NQTrp8 15 / 1 / 1 / 1
Cl-NQTrp1413 / 1 / 1 / 1
NQTrp315 / 1 / 1 / 1
Cl-NQTrp1513 / 1 / 1 / 1
Am-NQTrp213 / 1 / 1 / 0
NQTrp15 / 1 / 1 / 1
Cl-NQTrp13 / 1 / 1 / 1
Cl-NQTrp615 / 0 / 1 / 0
Cl-NQTrp1215 / 0 / 0 / 0
Cl-NQTrp415 / 0 / 1 / 0
Cl-NQTrp515 / 0 / 0 / 0
Cl-NQTrp1015 / 1 / 1 / 1
tetracycline6 / 0 / 0 / 0
D-Trp- D-Pro2 / 0 / 0 / 0
Tyr-Tyr-Pro2 / 0 / 0 / 0
2,3,4-trihydroxy benzophenone 9 / 1 / 1 / 1
1,2,4 benzentriol7 / 0 / 0 / 0
5-hydroxydopamine7 / 0 / 0 / 0
9-acetylcarbazole4 / 0 / 0 / 0

Table S2.Test set molecules.

DT
model / Bayesian
model / Observed
activity / Name
1 / 1 / 1 / apomorphin3
1 / 1 / 1 / catechin8
0 / 0 / 0 / daunomycinone6
0 / 0 / 0 / demeclocycline6
0 / 0 / 0 / direct Yellow 41
1 / 0 / 0 / ethyl gallate* 7
1 / 1 / 1 / hypericin9
0 / 0 / 0 / N-methylpyrrolidine11
0 / 0 / 0 / D-Phe-D-Phe-Aib2
0 / 0 / 0 / Pro-Tyr-Tyr-Pro2
1 / 1 / 1 / quercetin8
0 / 0 / 0 / SKF-630584
0 / 1 / 0 / Cl-NQTrp16** 13
0 / 1 / 0 / Cl-NQTrp17** 13
1 / 1 / 1 / Am-NQTrp115

* Compounds that were predicted falsely as positive by the DT model. ** Compounds that were predicted falsely as positive by the Bayesian model.

Table S3.List of descriptors calculated.

ALogP / Num_Bonds
ALogP_MR / Num_BridgeBonds
BIC / Num_BridgeHeadAtoms
CHI_0 / Num_ChainAssemblies
CHI_1 / Num_Chains
CHI_2 / Num_ExplicitHydrogens
CHI_3_C / Num_Fragments
CHI_3_CH / Num_H_Acceptors
CHI_3_P / Num_H_Acceptors_Lipinski
CHI_V_0 / Num_H_Donors
CHI_V_1 / Num_H_Donors_Lipinski
CHI_V_2 / Num_Hydrogens
CHI_V_3_C / Num_Macro_Chains
CHI_V_3_CH / Num_Macro_Residues
CHI_V_3_P / Num_MetalAtoms
IC / Num_NegativeAtoms
CIC / Num_PositiveAtoms
E_ADJ_equ / Num_RingAssemblies
E_ADJ_mag / Num_RingBonds
E_DIST_equ / Num_Rings
E_DIST_mag / Num_Rings3
Element Counts (various atom types) / Num_Rings4
ES_Count_xxx (various atom types) / Num_Rings5
ES_Sum_xxx (various atom types) / Num_Rings6
HBA_Count / Num_Rings7
HBD_Count / Num_Rings8
IAC_Mean / Num_Rings9Plus
IAC_Total / Num_RotatableBonds
JX / Num_SpiroAtoms
JY / Num_StereoAtoms
Kappa_1 / Num_StereoBonds
Kappa_1_AM / Num_TerminalRotomers
Kappa_2 / Num_TrueStereoAtoms
Kappa_2_AM / Num_UnknownStereoAtoms
Kappa_3 / Num_UnknownStereoBonds
Kappa_3_AM / Num_UnknownTrueStereoAtoms
Molecular_FractionalPolarSASA / Organic_Count
Molecular_FractionalPolarSurfaceArea / PHI
Molecular_Mass / RadOfGyration
Molecular_PolarSASA / SC_0
Molecular_PolarSurfaceArea / SC_1
Molecular_SASA / SC_2
Molecular_SAVol / SC_3_C
Molecular_Solubility / SC_3_P
Molecular_SurfaceArea / SC_3_PC
Molecular_Volume / SIC
Molecular_Weight / V_ADJ_equ
NPlusO_Count / V_ADJ_mag
Num_AromaticBonds / V_DIST_equ
Num_AromaticRings / V_DIST_mag
Num_AtomClasses / Wiener
Num_Atoms / Zagreb

Table S4.Compound attributes in training set.

Structural attribute / # of compounds that exhibit the attribute / # inhibitors / # non inhibitors
Monocyclic aromatic rings / 17 / 2 / 15
Polycyclic aromatic rings / 48 / 24 / 24
Non aromatic rings / 41 / 20 / 21
Nitrogen containing rings / 15 / 8 / 7
Oxygen containing rings / 10 / 6 / 4
Halogens / 13 / 5 / 8
Amines / 44 / 14 / 30

Table S5.WEKA-J48default parameters.

binarySplits / False
confidenceFactor / 0.25
debug / False
minNumObj / 2
numFolds / 3
reducedErrorPruning / False
saveInstanceData / False
seed / 1
subtreeRaising / True
unpruned / False
useLaplace / False

Table S6.Descriptors correlation matrix.

Property / IC / Num_AromaticBonds / ALogP / Molecular_PSA / ES_Sum_dO / HBD_count
IC / 1 / 0.20002 / 0.04907 / 0.39994 / 0.41284 / 0.15999
Num_AromaticBonds / 0.20002 / 1 / 0.64528 / 0.38595 / 0.44529 / -0.09311
ALogP / 0.04907 / 0.64528 / 1 / -0.11115 / 0.05747 / -0.50132
Molecular_PolarSurfaceArea / 0.39994 / 0.38595 / -0.11115 / 1 / 0.7757 / 0.46378
ES_Sum_dO / 0.41284 / 0.44529 / 0.05747 / 0.7757 / 1 / 0.01466
HBD_count / 0.15999 / -0.09311 / -0.50132 / 0.46378 / 0.01466 / 1

Figure S1. Molecular structures of three molecules that were tested experimentally in vitrofor Aβ aggregation inhibitory activity. (A) N,N'-bis(4-methylphenyl) ethanediamide (ABI-1), (B) 5,12-dihydroquinolino[2,3-b]acridine-7,14-dione (ABI-2), (C) N-(3-Indolylacetyl)-L-phenylalanine (ABI-3).

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