NPASS Compound

Natural Product: NPC476026

Natural Product ID	NPC476026
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Itoside C
IUPAC Name	[(2S,3R,4S,5R,6R)-3,5-dihydroxy-2-[4-hydroxy-2-[(1-hydroxy-6-oxocyclohex-2-ene-1-carbonyl)oxymethyl]phenoxy]-6-(hydroxymethyl)oxan-4-yl] benzoate
Synonyms	Itoside C
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL522364
PubChem CID	44577068
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0004603] Organic oxygen compounds [CHEMONTID:0000323] Organooxygen compounds [CHEMONTID:0000011] Carbohydrates and carbohydrate conjugates [CHEMONTID:0002105] Glycosyl compounds [CHEMONTID:0004165] Phenolic glycosides

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 67 70 0 0 0 0 0 0 0 0999 V2000 -0.3915 -3.3013 -2.2769 O 0 0 0 0 0 0 0 0 0 0 0 0 0.6533 -3.0957 -1.3536 C 0 0 0 0 0 0 0 0 0 0 0 0 1.0359 -1.6436 -1.4939 C 0 0 1 0 0 0 0 0 0 0 0 0 0.0022 -0.7602 -1.2205 O 0 0 0 0 0 0 0 0 0 0 0 0 0.0656 -0.2623 0.0894 C 0 0 1 0 0 0 0 0 0 0 0 0 0.0041 -1.2285 0.9852 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.5699 -1.8194 1.9992 C 0 0 0 0 0 0 0 0 0 0 0 0 0.0166 -2.9925 2.5098 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.4841 -3.6964 3.5581 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.6209 -3.2594 4.1669 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.2259 -2.1246 3.7059 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.7188 -1.3919 2.6272 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4653 -0.1847 2.2256 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.2181 -0.4215 1.0454 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.0084 0.5444 0.4512 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.0623 1.6785 0.9782 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.7707 0.2196 -0.7895 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.5357 -1.1157 -1.1552 O 0 0 0 0 0 0 0 0 0 0 0 0 -6.2132 0.4563 -0.5410 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.7751 1.5985 -0.8717 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.0379 2.7185 -1.5040 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.9686 2.2206 -2.4502 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2302 1.0696 -1.8812 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.1196 0.7764 -2.3067 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.1343 -3.9817 5.2423 O 0 0 0 0 0 0 0 0 0 0 0 0 1.2423 0.7171 0.2410 C 0 0 1 0 0 0 0 0 0 0 0 0 2.3331 0.1947 -0.6470 C 0 0 2 0 0 0 0 0 0 0 0 0 2.2847 -1.2882 -0.6805 C 0 0 2 0 0 0 0 0 0 0 0 0 3.4031 -1.8222 -1.3605 O 0 0 0 0 0 0 0 0 0 0 0 0 3.5941 0.7408 -0.3728 O 0 0 0 0 0 0 0 0 0 0 0 0 4.3488 1.5172 -1.2293 C 0 0 0 0 0 0 0 0 0 0 0 0 3.8486 1.7440 -2.3485 O 0 0 0 0 0 0 0 0 0 0 0 0 5.6680 2.0519 -0.8555 C 0 0 0 0 0 0 0 0 0 0 0 0 6.4100 2.8195 -1.7252 C 0 0 0 0 0 0 0 0 0 0 0 0 7.6626 3.3240 -1.3582 C 0 0 0 0 0 0 0 0 0 0 0 0 8.1881 3.0637 -0.1099 C 0 0 0 0 0 0 0 0 0 0 0 0 7.4424 2.2951 0.7578 C 0 0 0 0 0 0 0 0 0 0 0 0 6.1968 1.7962 0.3864 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8952 1.9896 -0.2611 O 0 0 0 0 0 0 0 0 0 0 0 0 0.0385 -3.2707 -3.1703 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4968 -3.7137 -1.6699 H 0 0 0 0 0 0 0 0 0 0 0 0 0.3524 -3.3830 -0.3357 H 0 0 0 0 0 0 0 0 0 0 0 0 1.2881 -1.4966 -2.5773 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.8259 0.4330 0.1279 H 0 0 0 0 0 0 0 0 0 0 0 0 0.9211 -3.3635 2.0451 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0140 -4.6132 3.9466 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1325 -1.8062 4.2168 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.8600 0.7415 2.1843 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2113 0.0385 3.0473 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.5780 -1.1414 -1.4731 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.8081 -0.3423 -0.0738 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.8482 1.6917 -0.6532 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.7652 3.2930 -2.1160 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.5423 3.3705 -0.7572 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.4766 1.9283 -3.3981 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.3082 3.0998 -2.6610 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.5948 -4.8735 5.0704 H 0 0 0 0 0 0 0 0 0 0 0 0 1.5224 0.8197 1.2925 H 0 0 0 0 0 0 0 0 0 0 0 0 2.0862 0.5356 -1.6984 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1617 -1.7374 0.3078 H 0 0 0 0 0 0 0 0 0 0 0 0 3.4264 -1.3995 -2.2456 H 0 0 0 0 0 0 0 0 0 0 0 0 5.9759 3.0109 -2.7037 H 0 0 0 0 0 0 0 0 0 0 0 0 8.2242 3.9247 -2.0623 H 0 0 0 0 0 0 0 0 0 0 0 0 9.1665 3.4710 0.1460 H 0 0 0 0 0 0 0 0 0 0 0 0 7.8324 2.0776 1.7404 H 0 0 0 0 0 0 0 0 0 0 0 0 5.6039 1.1847 1.0774 H 0 0 0 0 0 0 0 0 0 0 0 0 0.1238 2.3739 0.2167 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 1 0 5 6 1 0 6 7 1 0 7 8 2 0 8 9 1 0 9 10 2 0 10 11 1 0 11 12 2 0 12 13 1 0 13 14 1 0 14 15 1 0 15 16 2 0 15 17 1 0 17 18 1 0 17 19 1 0 19 20 2 0 20 21 1 0 21 22 1 0 22 23 1 0 23 24 2 0 10 25 1 0 5 26 1 0 26 27 1 0 27 28 1 0 28 29 1 0 27 30 1 0 30 31 1 0 31 32 2 0 31 33 1 0 33 34 2 0 34 35 1 0 35 36 2 0 36 37 1 0 37 38 2 0 26 39 1 0 28 3 1 0 38 33 1 0 12 7 1 0 23 17 1 0 1 40 1 0 2 41 1 0 2 42 1 0 3 43 1 6 5 44 1 1 8 45 1 0 9 46 1 0 11 47 1 0 13 48 1 0 13 49 1 0 18 50 1 0 19 51 1 0 20 52 1 0 21 53 1 0 21 54 1 0 22 55 1 0 22 56 1 0 25 57 1 0 26 58 1 1 27 59 1 6 28 60 1 1 29 61 1 0 34 62 1 0 35 63 1 0 36 64 1 0 37 65 1 0 38 66 1 0 39 67 1 0 M END

Standard InCHIKey	LZMZVGLTYMYFFB-SYCYEJLUSA-N
Standard InCHI	InChI=1S/C27H28O12/c28-13-19-21(31)23(39-24(33)15-6-2-1-3-7-15)22(32)25(38-19)37-18-10-9-17(29)12-16(18)14-36-26(34)27(35)11-5-4-8-20(27)30/h1-3,5-7,9-12,19,21-23,25,28-29,31-32,35H,4,8,13-14H2/t19-,21-,22-,23+,25-,27?/m1/s1
SMILES	OC[C@H]1O[C@@H](Oc2ccc(cc2COC(=O)C2(O)C=CCCC2=O)O)[C@@H]([C@H]([C@@H]1O)OC(=O)c1ccccc1)O

Calculated Properties

Physi-Chem Properties

Molecular Weight:	544.16	Volume:	520.44 ? Van der Waals volume.
Dense:	1.046	LogP:	0.663 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	1.43 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-2.527 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	10.0	Rigid Bonds:	27.0
TPSA:	189.28 ? Topological Polar Surface Area.	H-Bond Acceptor:	12.0
H-Bond Donor:	5.0	Rings:	4.0
Heavy Atoms:	12.0

MedChem Properties

QED Drug-Likeness Score:	0.172	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	4.35	Fsp³:	0.37
MCE-18:	92.676 ? MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.	Lipinski Rule-of-5:	Accepted
Pfizer Rule:	Rejected	GSK Rule:	Accepted
Golden Triangle Rule:	Accepted	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.496	Fluc inhibitor:	0.114 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.027 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.321 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.166	Promiscuous compounds:	0.46

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.919	MDCK Permeability:	-5.183
Pgp-inhibitor:	0.0	Pgp-substrate:	0.001
PAMPA:	0.994 ? 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):	0.038
20% Bioavailability (F20%):	0.093	30% Bioavailability (F30%):	0.991
50% Bioavailability (F50%):	0.884

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.035	MRP1:	0.32
Plasma Protein Binding (PPB):	72.812%	Volume Distribution (VD):	-0.44
Fu:	30.436% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	1.0
OATP1B3 inhibitor:	1.0	BCRP inhibitor:	0.0
BSEP inhibitor:	0.018

ADMET: Metabolism

CYP1A2-inhibitor:	0.0	CYP1A2-substrate:	0.001
CYP2C19-inhibitor:	0.0	CYP2C19-substrate:	0.0
CYP2C9-inhibitor:	0.0	CYP2C9-substrate:	0.0
CYP2D6-inhibitor:	0.0	CYP2D6-substrate:	0.031
CYP3A4-inhibitor:	0.773	CYP3A4-substrate:	0.257
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.996
HLM stability:	0.906 ? 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):

5.676

Half-life (T1/2):

2.244

ADMET: Toxicity

hERG Blockers:	0.014	hERG Blockers (10um):	0.085
Human Hepatotoxicity (H-HT):	0.22	Drug-induced Liver Injury (DILI):	0.587
AMES Toxicity:	0.748	Rat Oral Acute Toxicity:	0.017
Maximum Recommended Daily Dose:	0.093	Skin Sensitization:	0.988
Carcinogencity:	0.725	Eye Corrosion:	0.0
Eye Irritation:	0.015	Respiratory Toxicity:	0.004
Drug-induced Neurotoxicity:	0.022	Ototoxicity:	0.686
Hematotoxicity:	0.104	Drug-induced Nephrotoxicity:	0.782
Genotoxicity:	0.94	RPMI-8226 Immunitoxicity:	0.065
A549 Cytotoxicity:	0.074	Hek293 Cytotoxicity:	0.572
BCF:	0.489 ? 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:	3.291 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.628 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	3.983 ? 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
NPO9317	Itoa orientalis	Species	Salicaceae	Eukaryota	bark, twigs, and leaves	n.a.	n.a.	PMID[18412396]
NPO9317	Itoa orientalis	Species	Salicaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO9317	Itoa orientalis	Species	Salicaceae	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
Inhibition	1

Activity Type	# Activity
Individual protein	1

Molecular-level activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT31	Individual protein	Cyclooxygenase-2	Homo sapiens	Inhibition	=	70.7	%	PubChem BioAssay data set

In vitro activity

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

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 NPC476026 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	11883
0.1-0.2	34605
0.2-0.3	3297
0.3-0.4	44
0.4-0.5	15
0.5-0.6	6
0.6-0.7	6
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
0.7614	Intermediate Similarity	NPC474398
0.7416	Intermediate Similarity	NPC474401
0.6957	Remote Similarity	NPC474441
0.6744	Remote Similarity	NPC474422
0.6702	Remote Similarity	NPC475183
0.6552	Remote Similarity	NPC299761
0.6022	Remote Similarity	NPC131874
0.602	Remote Similarity	NPC280923
0.5938	Remote Similarity	NPC71780
0.5596	Remote Similarity	NPC475174
0.5319	Remote Similarity	NPC471214
0.5248	Remote Similarity	NPC57072
0.5176	Remote Similarity	NPC31081
0.5111	Remote Similarity	NPC92054

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC476026 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	3468
0.1-0.2	5576
0.2-0.3	106
0.3-0.4	0
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