NPASS Compound

Natural Product: NPC477922

Natural Product ID	NPC477922
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	[(3aS,4S,5R,6E,10E,11aR)-5-ethoxy-6-formyl-10-(hydroxymethyl)-3-methylidene-2-oxo-3a,4,5,8,9,11a-hexahydrocyclodeca[b]furan-4-yl] 2-methylprop-2-enoate
IUPAC Name	[(3aS,4S,5R,6E,10E,11aR)-5-ethoxy-6-formyl-10-(hydroxymethyl)-3-methylidene-2-oxo-3a,4,5,8,9,11a-hexahydrocyclodeca[b]furan-4-yl] 2-methylprop-2-enoate
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	n.a.
PubChem CID	118708060
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000012] Lipids and lipid-like molecules [CHEMONTID:0000259] Prenol lipids [CHEMONTID:0001283] Terpene lactones [CHEMONTID:0001543] Sesquiterpene lactones [CHEMONTID:0001771] Germacranolides and derivatives

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

Chemical Representations

RDKit 2D 54 55 0 0 0 0 0 0 0 0999 V2000 -7.2058 1.5271 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.7140 1.3703 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2222 1.2135 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.3405 2.4271 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4589 1.2135 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0323 0.7500 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3943 1.2135 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 1.2760 2.4271 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 1.2760 3.9271 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3943 5.1406 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0323 5.6041 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4589 5.1406 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.3405 3.9271 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.7671 4.3906 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.0790 5.8578 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 2.7026 4.3906 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 4.1291 4.8541 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 1.2760 0.0000 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 0.3943 -1.2135 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8578 -2.6401 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.0323 -0.7500 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.2458 -1.6317 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4589 -0.2865 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.7579 -1.0365 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.1387 -0.4504 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.7579 -2.5365 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4589 -3.2865 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.0569 -3.2865 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0 -7.0490 3.0189 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.3626 0.0353 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -8.6976 1.6839 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.0515 -0.0912 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.8832 2.5735 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7000 3.0610 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7309 0.4186 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6016 0.0715 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 1.8943 1.2135 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 2.7026 1.9635 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4954 5.6541 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 0.5771 6.6294 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.3051 6.9161 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9140 6.8176 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3405 6.3541 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.7624 3.6937 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 2.4708 5.5833 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 3.1661 2.9640 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 4.4410 6.3213 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.8302 -2.7734 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2150 -1.4608 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4589 -4.7865 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1598 -2.5365 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.3069 -4.5855 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.8069 -1.9874 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.3560 -4.0365 0.0000 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 1 0 8 9 2 0 9 10 1 0 10 11 1 0 11 12 1 0 12 13 2 0 13 14 1 0 14 15 2 0 9 16 1 0 16 17 1 0 7 18 1 0 18 19 1 0 19 20 2 0 19 21 1 0 21 22 2 0 5 23 1 0 23 24 1 0 24 25 2 0 24 26 1 0 26 27 2 0 26 28 1 0 13 4 1 0 21 6 1 0 1 29 1 0 1 30 1 0 1 31 1 0 2 32 1 0 2 33 1 0 4 34 1 1 5 35 1 1 6 36 1 1 7 37 1 6 8 38 1 0 10 39 1 0 10 40 1 0 11 41 1 0 11 42 1 0 12 43 1 0 14 44 1 0 16 45 1 0 16 46 1 0 17 47 1 0 22 48 1 0 22 49 1 0 27 50 1 0 27 51 1 0 28 52 1 0 28 53 1 0 28 54 1 0 M END

Standard InCHIKey	JSCXGQXFCTYXGO-YCVKBKJGSA-N
Standard InCHI	InChI=1S/C21H26O7/c1-5-26-18-15(11-23)8-6-7-14(10-22)9-16-17(13(4)21(25)27-16)19(18)28-20(24)12(2)3/h8-9,11,16-19,22H,2,4-7,10H2,1,3H3/b14-9+,15-8-/t16-,17+,18-,19+/m1/s1
SMILES	CCO[C@H]/1[C@H]([C@@H]2[C@@H](/C=C(\CC/C=C1/C=O)/CO)OC(=O)C2=C)OC(=O)C(=C)C

Calculated Properties

Physi-Chem Properties

Molecular Weight:	390.17	Volume:	397.736 ? Van der Waals volume.
Dense:	0.981	LogP:	1.349 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	1.687 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-2.725 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	7.0	Rigid Bonds:	19.0
TPSA:	99.13 ? Topological Polar Surface Area.	H-Bond Acceptor:	7.0
H-Bond Donor:	1.0	Rings:	2.0
Heavy Atoms:	7.0

MedChem Properties

QED Drug-Likeness Score:	0.32	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	5.126	Fsp³:	0.476
MCE-18:	38.194 ? MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.	Lipinski Rule-of-5:	Rejected
Pfizer Rule:	Rejected	GSK Rule:	Rejected
Golden Triangle Rule:	Rejected	BMS Rule:	1
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.378	Fluc inhibitor:	0.002 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.067 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.147 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.489	Promiscuous compounds:	0.375

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.941	MDCK Permeability:	-4.716
Pgp-inhibitor:	0.025	Pgp-substrate:	0.007
PAMPA:	0.839 ? 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):	0.582
20% Bioavailability (F20%):	0.757	30% Bioavailability (F30%):	0.983
50% Bioavailability (F50%):	0.99

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.004	MRP1:	0.256
Plasma Protein Binding (PPB):	69.298%	Volume Distribution (VD):	0.089
Fu:	30.719% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.997
OATP1B3 inhibitor:	0.999	BCRP inhibitor:	0.018
BSEP inhibitor:	0.754

ADMET: Metabolism

CYP1A2-inhibitor:	0.0	CYP1A2-substrate:	0.414
CYP2C19-inhibitor:	0.0	CYP2C19-substrate:	0.197
CYP2C9-inhibitor:	0.033	CYP2C9-substrate:	0.004
CYP2D6-inhibitor:	0.003	CYP2D6-substrate:	0.053
CYP3A4-inhibitor:	0.005	CYP3A4-substrate:	0.122
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.972
HLM stability:	0.74 ? 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):

6.492

Half-life (T1/2):

1.209

ADMET: Toxicity

hERG Blockers:	0.007	hERG Blockers (10um):	0.059
Human Hepatotoxicity (H-HT):	0.697	Drug-induced Liver Injury (DILI):	0.908
AMES Toxicity:	0.689	Rat Oral Acute Toxicity:	0.067
Maximum Recommended Daily Dose:	0.335	Skin Sensitization:	0.998
Carcinogencity:	0.734	Eye Corrosion:	0.019
Eye Irritation:	0.961	Respiratory Toxicity:	0.141
Drug-induced Neurotoxicity:	0.33	Ototoxicity:	0.294
Hematotoxicity:	0.327	Drug-induced Nephrotoxicity:	0.917
Genotoxicity:	0.968	RPMI-8226 Immunitoxicity:	0.13
A549 Cytotoxicity:	0.076	Hek293 Cytotoxicity:	0.236
BCF:	0.711 ? 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:	3.519 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.5 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.789 ? 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
NPO30031	Siegesbeckia pubescens	Species	Asteraceae	Eukaryota	aerial parts	n.a.	n.a.	PMID[19928884]
NPO30031	Siegesbeckia pubescens	Species	Asteraceae	Eukaryota	aerial part	n.a.	n.a.	PMID[24997688]
NPO30031	Siegesbeckia pubescens	Species	Asteraceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO30031	Siegesbeckia pubescens	Species	Asteraceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCM_Taiwan]

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	3
Inhibition	2

Activity Type	# Activity
Cell line	1
Others	4

Molecular-level activity

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

In vitro activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT113	Cell line	RAW264.7	Mus musculus	IC50	=	6800	nM	PMID[24997688]
NPT2	Others	Unspecified	n.a.	Inhibition	=	72.42	%	PMID[24997688]
NPT2	Others	Unspecified	n.a.	IC50	=	6.46	ug/ml	PMID[24997688]
NPT2	Others	Unspecified	n.a.	Inhibition	=	22.26	%	PMID[24997688]
NPT2	Others	Unspecified	n.a.	IC50	>	10	ug/ml	PMID[24997688]

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 NPC477922 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	15987
0.1-0.2	30271
0.2-0.3	3251
0.3-0.4	296
0.4-0.5	38
0.5-0.6	5
0.6-0.7	5
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
0.7778	Intermediate Similarity	NPC599997
0.7778	Intermediate Similarity	NPC601440
0.7778	Intermediate Similarity	NPC601519
0.7455	Intermediate Similarity	NPC603351
0.7091	Intermediate Similarity	NPC610116
0.6607	Remote Similarity	NPC477921
0.6491	Remote Similarity	NPC607796
0.6491	Remote Similarity	NPC608869
0.6316	Remote Similarity	NPC602288
0.6034	Remote Similarity	NPC600706
0.55	Remote Similarity	NPC473390
0.541	Remote Similarity	NPC158756
0.541	Remote Similarity	NPC601035
0.5156	Remote Similarity	NPC469910
0.5085	Remote Similarity	NPC24417

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC477922 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	5697
0.1-0.2	3409
0.2-0.3	43
0.3-0.4	1
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