NPASS Compound

Natural Product: NPC144027

Natural Product ID	NPC144027
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Olympicin A
IUPAC Name	(2S)-1-[2-[(2E)-3,7-dimethylocta-2,6-dienoxy]-4,6-dihydroxyphenyl]-2-methylbutan-1-one
Synonyms	Olympicin A
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL2023358
PubChem CID	57380109
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0004603] Organic oxygen compounds [CHEMONTID:0000323] Organooxygen compounds [CHEMONTID:0001831] Carbonyl compounds [CHEMONTID:0000118] Ketones [CHEMONTID:0003670] Aryl ketones [CHEMONTID:0004296] Phenylketones [CHEMONTID:0004298] Alkyl-phenylketones

The Chemical Classification was calculated by Classyfire, a software for chemical taxonomy calculation. Reference: DOI:10.1186/s13321-016-0174-y.

Chemical Representations

RDKit 3D 55 55 0 0 0 0 0 0 0 0999 V2000 5.7377 0.8820 1.7498 C 0 0 0 0 0 0 0 0 0 0 0 0 5.9099 0.6025 0.2654 C 0 0 0 0 0 0 0 0 0 0 0 0 4.8236 1.1838 -0.5587 C 0 0 1 0 0 0 0 0 0 0 0 0 3.4639 0.7309 -0.2887 C 0 0 0 0 0 0 0 0 0 0 0 0 2.7514 1.5776 0.3853 O 0 0 0 0 0 0 0 0 0 0 0 0 2.8423 -0.5029 -0.6700 C 0 0 0 0 0 0 0 0 0 0 0 0 1.5176 -0.7506 -0.2440 C 0 0 0 0 0 0 0 0 0 0 0 0 0.9448 0.2146 0.5367 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.3576 0.1380 1.0112 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4253 0.1726 -0.0153 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.3450 1.1610 0.0184 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4404 1.2559 -0.9775 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.7657 1.1769 -0.2170 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.8570 -0.1185 0.5248 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.8389 -0.9699 0.2684 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.8563 -0.6325 -0.7649 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.8858 -2.2403 1.0301 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.2345 2.1706 1.0912 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8979 -1.9147 -0.6225 C 0 0 0 0 0 0 0 0 0 0 0 0 1.5452 -2.8639 -1.4226 C 0 0 0 0 0 0 0 0 0 0 0 0 2.8281 -2.5895 -1.8173 C 0 0 0 0 0 0 0 0 0 0 0 0 3.5029 -1.4144 -1.4554 C 0 0 0 0 0 0 0 0 0 0 0 0 4.8008 -1.2098 -1.8993 O 0 0 0 0 0 0 0 0 0 0 0 0 0.8441 -3.9915 -1.7470 O 0 0 0 0 0 0 0 0 0 0 0 0 4.9499 2.7142 -0.3944 C 0 0 0 0 0 0 0 0 0 0 0 0 5.5796 1.9379 1.9739 H 0 0 0 0 0 0 0 0 0 0 0 0 6.7291 0.6047 2.2155 H 0 0 0 0 0 0 0 0 0 0 0 0 5.0029 0.1951 2.2172 H 0 0 0 0 0 0 0 0 0 0 0 0 6.1649 -0.4346 0.1720 H 0 0 0 0 0 0 0 0 0 0 0 0 6.8475 1.1757 -0.0118 H 0 0 0 0 0 0 0 0 0 0 0 0 5.0536 1.0275 -1.6342 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.4630 -0.8841 1.5086 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5639 0.8423 1.8484 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5714 -0.5159 -0.8275 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.4417 2.2217 -1.5225 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.4126 0.4447 -1.7055 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.8468 1.9887 0.5337 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.6268 1.2766 -0.9207 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.0982 -0.3125 1.2592 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.3933 0.2996 -0.5325 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.5411 -1.4802 -0.8635 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.3386 -0.4834 -1.7337 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.3743 -3.0101 0.4147 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.2998 -2.1449 1.9662 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.9396 -2.5472 1.2494 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1954 2.5856 1.0487 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3955 1.6652 2.0610 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9858 2.9892 0.9278 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.1182 -2.1227 -0.2726 H 0 0 0 0 0 0 0 0 0 0 0 0 3.3400 -3.3058 -2.4310 H 0 0 0 0 0 0 0 0 0 0 0 0 5.0775 -1.1837 -2.8593 H 0 0 0 0 0 0 0 0 0 0 0 0 1.3327 -4.8020 -2.1255 H 0 0 0 0 0 0 0 0 0 0 0 0 6.0404 2.9190 -0.4220 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5750 3.0419 0.5830 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5089 3.2298 -1.2574 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 2 3 1 0 3 4 1 0 4 5 2 0 4 6 1 0 6 7 2 0 7 8 1 0 8 9 1 0 9 10 1 0 10 11 2 0 11 12 1 0 12 13 1 0 13 14 1 0 14 15 2 3 15 16 1 0 15 17 1 0 11 18 1 0 7 19 1 0 19 20 2 0 20 21 1 0 21 22 2 0 22 23 1 0 20 24 1 0 3 25 1 0 22 6 1 0 1 26 1 0 1 27 1 0 1 28 1 0 2 29 1 0 2 30 1 0 3 31 1 6 9 32 1 0 9 33 1 0 10 34 1 0 12 35 1 0 12 36 1 0 13 37 1 0 13 38 1 0 14 39 1 0 16 40 1 0 16 41 1 0 16 42 1 0 17 43 1 0 17 44 1 0 17 45 1 0 18 46 1 0 18 47 1 0 18 48 1 0 19 49 1 0 21 50 1 0 23 51 1 0 24 52 1 0 25 53 1 0 25 54 1 0 25 55 1 0 M END

Standard InCHIKey	UMIJNJJRYSRDPG-KMPOOHAWSA-N
Standard InCHI	InChI=1S/C21H30O4/c1-6-16(5)21(24)20-18(23)12-17(22)13-19(20)25-11-10-15(4)9-7-8-14(2)3/h8,10,12-13,16,22-23H,6-7,9,11H2,1-5H3/b15-10+/t16-/m0/s1
SMILES	CC[C@@H](C(=O)c1c(OC/C=C(/CCC=C(C)C)C)cc(cc1O)O)C

Calculated Properties

Physi-Chem Properties

Molecular Weight:	346.21	Volume:	382.558 ? Van der Waals volume.
Dense:	0.905	LogP:	5.75 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	3.944 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-4.71 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	9.0	Rigid Bonds:	9.0
TPSA:	66.76 ? Topological Polar Surface Area.	H-Bond Acceptor:	4.0
H-Bond Donor:	2.0	Rings:	1.0
Heavy Atoms:	4.0

MedChem Properties

QED Drug-Likeness Score:	0.464	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	3.276	Fsp³:	0.476
MCE-18:	22.0 ? MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.	Lipinski Rule-of-5:	Rejected
Pfizer Rule:	Accepted	GSK Rule:	Accepted
Golden Triangle Rule:	Rejected	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.507	Fluc inhibitor:	0.226 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.282 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.363 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.707	Promiscuous compounds:	0.201

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.776	MDCK Permeability:	-4.604
Pgp-inhibitor:	0.74	Pgp-substrate:	0.255
PAMPA:	0.029 ? The experimental data for Peff was logarithmically transformed (logPeff). Molecules with log Peff values below 2.0 were classified as low-permeability (Category 0), while those with log Peff values exceeding 2.5 were classified as high-permeability (Category 1).	Human Intestinal Absorption (HIA):	0.001
20% Bioavailability (F20%):	0.481	30% Bioavailability (F30%):	0.99
50% Bioavailability (F50%):	0.998

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.001	MRP1:	0.711
Plasma Protein Binding (PPB):	95.953%	Volume Distribution (VD):	0.164
Fu:	4.044% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.996
OATP1B3 inhibitor:	0.975	BCRP inhibitor:	0.991
BSEP inhibitor:	0.221

ADMET: Metabolism

CYP1A2-inhibitor:	0.398	CYP1A2-substrate:	0.946
CYP2C19-inhibitor:	0.374	CYP2C19-substrate:	0.421
CYP2C9-inhibitor:	0.009	CYP2C9-substrate:	0.01
CYP2D6-inhibitor:	0.055	CYP2D6-substrate:	0.735
CYP3A4-inhibitor:	0.004	CYP3A4-substrate:	0.996
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	1.0
HLM stability:	0.841 ? Human liver microsomal (HLM) stability. Category 0: stable+ (HLM > 30 min); Category 1: unstable- (HLM ≤ 30 min). The output value is the probability of human liver microsomal instability, where a value closer to 1 indicates a higher likelihood of instability.

ADMET: Excretion

Clearance (CL):

8.55

Half-life (T1/2):

0.862

ADMET: Toxicity

hERG Blockers:	0.207	hERG Blockers (10um):	0.56
Human Hepatotoxicity (H-HT):	0.535	Drug-induced Liver Injury (DILI):	0.318
AMES Toxicity:	0.221	Rat Oral Acute Toxicity:	0.201
Maximum Recommended Daily Dose:	0.531	Skin Sensitization:	0.989
Carcinogencity:	0.29	Eye Corrosion:	0.01
Eye Irritation:	0.891	Respiratory Toxicity:	0.965
Drug-induced Neurotoxicity:	0.579	Ototoxicity:	0.437
Hematotoxicity:	0.247	Drug-induced Nephrotoxicity:	0.292
Genotoxicity:	0.431	RPMI-8226 Immunitoxicity:	0.115
A549 Cytotoxicity:	0.351	Hek293 Cytotoxicity:	0.469
BCF:	2.192 ? Bioconcentration factors are used for considering secondary poisoning potential and assessing risks to human health via the food chain. The unit is -log10[(mg/L)/(1000*MW)].	IGC50:	4.825 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	6.344 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	5.825 ? 96 hour fathead minnow LC50. The unit of LC50FM is -log10[(mg/L)/(1000*MW)].

Species Source

Organism ID	Organism Name	Taxonomy Level	Family	SuperKingdom	Isolation Part	Collection Location	Collection Time	Reference
NPO22037	Hypericum olympicum	Species	Hypericaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[21899267]
NPO22037	Hypericum olympicum	Species	Hypericaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO22037	Hypericum olympicum	Species	Hypericaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]

Note for Reference:
In addition to directly collecting NP source organism data from primary literature (where reference will provided as NCBI PMID or DOI links), NPASS also integrated them from below databases:
☉ UNPD: Universal Natural Products Database [PMID: 23638153].
☉ StreptomeDB: a database of streptomycetes natural products [PMID: 33051671].
☉ TM-MC: a database of medicinal materials and chemical compounds in Northeast Asian traditional medicine [PMID: 26156871].
☉ TCM@Taiwan: a Traditional Chinese Medicine database [PMID: 21253603].
☉ TCMID: a Traditional Chinese Medicine database [PMID: 29106634].
☉ TCMSP: The traditional Chinese medicine systems pharmacology database and analysis platform [PMID: 24735618].
☉ HerDing: a herb recommendation system to treat diseases using genes and chemicals [PMID: 26980517].
☉ MetaboLights: a metabolomics database [PMID: 27010336].
☉ FooDB: a database of constituents, chemistry and biology of food species [www.foodb.ca].

NP Quantity Composition/Concentration

Organism ID	Organism Name	Organism Material Preparation	Organism Part	NP Quantity (Standard)	NP Quantity (Minimum)	NP Quantity (Maximum)	Quantity Unit	Reference

Note for Reference:
In addition to directly collecting NP quantitative data from primary literature (where reference will provided as NCBI PMID or DOI links), NPASS also integrated NP quantitative records for specific NP domains (e.g., NPS from foods or herbs) from domain-specific databases. These databases include:
☉ DUKE: Dr. Duke's Phytochemical and Ethnobotanical Databases.
☉ PHENOL EXPLORER: is the first comprehensive database on polyphenol content in foods [PMID: 24103452], its homepage can be accessed at here.
☉ FooDB: a database of constituents, chemistry and biology of food species [www.foodb.ca].

Biological Activity

Activity Type	# Activity
IC50	7
MIC	30

Activity Type	# Activity
Cell line	3
Organism	30
Protein complex	1
Single protein	1
Others	2

Molecular-level activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT29994	Single protein	UDP-N-acetylmuramoyl-L-alanyl-D-glutamate--2,6-diaminopimelate ligase	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	IC50	=	75000.0	nM	PMID[36731248]
NPT1567	Protein complex	DNA gyrase	Escherichia coli K-12	IC50	=	500000.0	nM	PMID[16499317]

In vitro activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT1374	Cell line	WI-38	Homo sapiens	IC50	=	8900.0	nM	PMID[36731248]
NPT83	Cell line	MCF7	Homo sapiens	IC50	=	12500.0	nM	PMID[36731248]
NPT81	Cell line	A549	Homo sapiens	IC50	=	10500.0	nM	PMID[36731248]
NPT566	Organism	Salmonella typhimurium	Salmonella enterica subsp. enterica serovar Typhimurium	MIC	>	1000000.0	nM	PMID[22951040]
NPT602	Organism	Mycobacterium smegmatis	Mycobacterium smegmatis	MIC	=	11600.0	nM	PMID[17371827]
NPT1176	Organism	Mycobacterium fortuitum	Mycobacterium fortuitum	MIC	=	23200.0	nM	PMID[4020828]
NPT1466	Organism	Escherichia coli K12	Escherichia coli K-12	MIC	>	200.0	ug.mL-1	PMID[16872154]
NPT173	Organism	Klebsiella pneumoniae	Klebsiella pneumoniae	MIC	>	200.0	ug.mL-1	PMID[18710917]
NPT1548	Organism	Pseudomonas aeruginosa PAO1	Pseudomonas aeruginosa PAO1	MIC	>	200.0	ug.mL-1	PMID[18973387]
NPT16	Organism	Staphylococcus aureus	Staphylococcus aureus	MIC	=	2900.0	nM	PMID[4020828]
NPT16	Organism	Staphylococcus aureus	Staphylococcus aureus	MIC	=	1450.0	nM	PMID[23701598]
NPT1177	Organism	Mycobacterium phlei	Mycobacterium phlei	MIC	=	11600.0	nM	PMID[4020828]
NPT18	Organism	Pseudomonas aeruginosa	Pseudomonas aeruginosa	MIC	>	1000000.0	nM	PubChem BioAssay data set
NPT175	Organism	Enterococcus faecalis	Enterococcus faecalis	MIC	=	1.56	ug.mL-1	PMID[12608857]
NPT16	Organism	Staphylococcus aureus	Staphylococcus aureus	MIC	=	1.56	ug.mL-1	PMID[17850214]
NPT19	Organism	Escherichia coli	Escherichia coli	MIC	>	200.0	ug.mL-1	PMID[12161151]
NPT16	Organism	Staphylococcus aureus	Staphylococcus aureus	MIC	=	0.5	ug.mL-1	PMID[29890387]
NPT16	Organism	Staphylococcus aureus	Staphylococcus aureus	MIC	=	1.0	ug.mL-1	PMID[29890387]
NPT790	Organism	Mycobacterium tuberculosis H37Rv	Mycobacterium tuberculosis H37Rv	MIC	=	200.0	ug.mL-1	PMID[16933872]
NPT2	Others	Unspecified	n.a.	IC50	=	30000.0	nM	PMID[15332845]
NPT2	Others	Unspecified	n.a.	IC50	>	500000.0	nM	DOI[10.6019/CHEMBL1201861]
NPT1477	Organism	Staphylococcus haemolyticus	Staphylococcus haemolyticus	MIC	>	32.0	ug.mL-1	PMID[36731248]
NPT1477	Organism	Staphylococcus haemolyticus	Staphylococcus haemolyticus	MIC	>=	16.0	ug.mL-1	PMID[36731248]

In vivo activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference

Experimental ADME

Experiment Model	Experiment Tissue	ADME Type	ADME Relation	ADME Value	ADME Unit	Reference

Experimental Toxicity

Quantitative toxicity

Experiment Model	Experiment Organism	Toxicity Type	Toxicity Relation	Toxicity Value	Toxicity Unit	Reference

Common Abbreviations:
LC: Lethal Concentration; LD: Lethal Dose; LT:Lethal Time; NOAEL: No-observed-adverse-effect Level; BMDL: Benchmark Dose Lower Confidence Limit; BMD: Benchmark Dose; BMC:Benchmark Concentration; LOAEL: Lowest Observed Adverse Effect Level; RfD:Reference Dose; RfC:Reference Concentration; MRL: Minimal Risk Level; MEG: Maximum Exposure Guideline; PAC: Protective Action Criteria

Categorical toxicity labels

Hepatotoxicity	Carcinogenicity	Mutagenicity	Cardiotoxicity	Respiratory Toxicity	Eye Irritation	Endocrine Disruption

Note for Reference:
In addition to directly collecting NP quantitative data from primary literature (where reference will provided as NCBI PMID or DOI links), NPASS also integrated NP toxicity records from domain-specific databases. These databases include:
☉ ToxValDB: a curated database that compiles quantitative toxicity values for chemicals from diverse public sources to support toxicological research and risk assessment.
☉ TOXRIC: a comprehensive, free-to-access, online database providing toxicological/feature data. The toxicity labels are retrieved from this database. [PMID: 36400569]

Chemically structural similarity

Similar Active Natural Products in NPASS

Top-200 similar NPs were calculated against the active-NP-set (includes approximately 50,000 NPs with experimentally-derived bioactivity available in NPASS)

Similarity is measured using the Tanimoto coefficient (Tc) , which compares the binary fingerprints of two molecules. Tc is calculated as the intersection divided by the union of '1' bits in the fingerprints, ranging from 0 to 1, with 1 indicating highest similarity.

● The left chart: Distribution of similarity level between NPC144027 and all remaining natural products in the NPASS database.
● The right table: Most similar natural products (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	10542
0.1-0.2	35018
0.2-0.3	3835
0.3-0.4	397
0.4-0.5	52
0.5-0.6	7
0.6-0.7	3
0.7-0.8	0
0.8-0.85	0
0.85-0.9	0
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.7818	Intermediate Similarity	NPC240147
0.7414	Intermediate Similarity	NPC470399
0.7414	Intermediate Similarity	NPC470397
0.7288	Intermediate Similarity	NPC470398
0.6949	Remote Similarity	NPC187826
0.6271	Remote Similarity	NPC156910
0.614	Remote Similarity	NPC236974
0.5893	Remote Similarity	NPC203817
0.5538	Remote Similarity	NPC307990
0.55	Remote Similarity	NPC121243
0.5373	Remote Similarity	NPC23257
0.5294	Remote Similarity	NPC91902
0.5147	Remote Similarity	NPC484050
0.5143	Remote Similarity	NPC471587

Similar Clinical/Approved Drugs

Similarity level is defined by Tanimoto coefficient (Tc) between two molecules.

● The left chart: Distribution of similarity level between NPC144027 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	3212
0.1-0.2	5839
0.2-0.3	94
0.3-0.4	5
0.4-0.5	0
0.5-0.6	0
0.6-0.7	0
0.7-0.8	0
0.8-0.85	0
0.85-0.9	0
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Drug ID	Developmental Stage
		NPD

Bioactivity similarity

Similar Natural Products in NPASS

Similarity level is defined by Bioactivity similarity was calculated based on bioactivity descriptors of compounds. The bioactivity descriptors were calculated by a recently developed AI algorithm Chemical Checker (CC) [Nature Biotechnology, 38:1087–1096, 2020; Nature Communications, 12:3932, 2021], which evaluated bioactivity similarities at five levels:
☉ A: chemistry similarity;
☉ B: biological targets similarity;
☉ C: networks similarity;
☉ D: cell-based bioactivity similarity;
☉ E: similarity based on clinical data.
Those 5 categories of CC bioactivity descriptors were calculated and then subjected to manifold projection using UMAP algorithm, to project all NPs on a 2-Dimensional space. The current NP was highlighted with a small circle in the 2-D map. Below figures: left-to-right, A-to-E.

A: chemistry similarity

B: biological targets similarity

C: networks similarity

D: cell-based bioactivity similarity

E: similarity based on clinical data