NPASS Compound

Natural Product: NPC275950

Natural Product ID	NPC275950
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	4,4'-Dihydroxy-3,3'-Dimethoxy-9-Ethoxy-9,9'-Epoxylignan
IUPAC Name	4-[[(3R,4R,5S)-5-ethoxy-4-[(4-hydroxy-3-methoxyphenyl)methyl]oxolan-3-yl]methyl]-2-methoxyphenol
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL574119
PubChem CID	25156703
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0001392] Lignans, neolignans and related compounds [CHEMONTID:0003686] Furanoid lignans [CHEMONTID:0001604] Tetrahydrofuran lignans [CHEMONTID:0003424] 9,9'-epoxylignans

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 56 58 0 0 0 0 0 0 0 0999 V2000 0.0264 -3.1638 2.6761 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.2566 -1.7014 2.5830 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0432 -1.4345 1.4648 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.3759 -1.8379 0.3459 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.2760 -0.8023 -0.7518 C 0 0 2 0 0 0 0 0 0 0 0 0 -1.6252 -0.4669 -1.2900 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.5835 0.0836 -0.3155 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4584 -0.7102 0.3944 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.3453 -0.1607 1.3058 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.3821 1.1975 1.5326 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5244 1.9942 0.8392 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.6345 1.4358 -0.0763 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5574 3.3552 1.0626 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.7109 4.2715 0.3962 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.2641 1.7555 2.4406 O 0 0 0 0 0 0 0 0 0 0 0 0 0.4024 -1.6735 -1.8203 C 0 0 1 0 0 0 0 0 0 0 0 0 1.8714 -1.7734 -1.6655 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6219 -0.5228 -1.7274 C 0 0 0 0 0 0 0 0 0 0 0 0 3.1017 -0.0017 -2.9101 C 0 0 0 0 0 0 0 0 0 0 0 0 3.8115 1.1729 -2.9755 C 0 0 0 0 0 0 0 0 0 0 0 0 4.0748 1.8880 -1.8347 C 0 0 0 0 0 0 0 0 0 0 0 0 3.6032 1.3890 -0.6167 C 0 0 0 0 0 0 0 0 0 0 0 0 2.8905 0.2010 -0.5863 C 0 0 0 0 0 0 0 0 0 0 0 0 3.8670 2.1090 0.5415 O 0 0 0 0 0 0 0 0 0 0 0 0 3.3854 1.5944 1.7643 C 0 0 0 0 0 0 0 0 0 0 0 0 4.7964 3.0864 -1.8844 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.2005 -3.0371 -1.4813 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0269 -2.8592 -0.3780 O 0 0 0 0 0 0 0 0 0 0 0 0 1.1045 -3.3891 2.4360 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.2197 -3.5239 3.7127 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5679 -3.7039 1.9131 H 0 0 0 0 0 0 0 0 0 0 0 0 0.7097 -1.1622 2.4172 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.6852 -1.2729 3.5102 H 0 0 0 0 0 0 0 0 0 0 0 0 0.6218 -2.2770 0.5880 H 0 0 0 0 0 0 0 0 0 0 0 0 0.3352 0.0675 -0.4846 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.4913 0.2256 -2.1745 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.0567 -1.3959 -1.7695 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.4755 -1.7827 0.2556 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.0250 -0.7891 1.8558 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9792 2.1242 -0.5946 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.6309 4.0525 -0.7005 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.0353 5.3163 0.5700 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6896 4.1649 0.8093 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.9959 1.9198 3.3919 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0663 -1.3437 -2.8009 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1544 -2.3015 -0.7422 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2477 -2.4251 -2.5055 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9051 -0.5476 -3.8121 H 0 0 0 0 0 0 0 0 0 0 0 0 4.1805 1.5617 -3.9355 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5521 -0.1392 0.3798 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2636 1.6237 1.7126 H 0 0 0 0 0 0 0 0 0 0 0 0 3.6712 2.2897 2.5792 H 0 0 0 0 0 0 0 0 0 0 0 0 3.6903 0.5567 1.9346 H 0 0 0 0 0 0 0 0 0 0 0 0 4.2929 3.9415 -2.0314 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7149 -3.4133 -2.3647 H 0 0 0 0 0 0 0 0 0 0 0 0 0.5839 -3.7654 -1.1832 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 11 13 1 0 13 14 1 0 10 15 1 0 5 16 1 0 16 17 1 0 17 18 1 0 18 19 2 0 19 20 1 0 20 21 2 0 21 22 1 0 22 23 2 0 22 24 1 0 24 25 1 0 21 26 1 0 16 27 1 0 27 28 1 0 28 4 1 0 12 7 1 0 23 18 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 0 6 37 1 0 8 38 1 0 9 39 1 0 12 40 1 0 14 41 1 0 14 42 1 0 14 43 1 0 15 44 1 0 16 45 1 6 17 46 1 0 17 47 1 0 19 48 1 0 20 49 1 0 23 50 1 0 25 51 1 0 25 52 1 0 25 53 1 0 26 54 1 0 27 55 1 0 27 56 1 0 M END

Standard InCHIKey	MIRHQPXXACNGLB-JKSBSHDWSA-N
Standard InCHI	InChI=1S/C22H28O6/c1-4-27-22-17(10-15-6-8-19(24)21(12-15)26-3)16(13-28-22)9-14-5-7-18(23)20(11-14)25-2/h5-8,11-12,16-17,22-24H,4,9-10,13H2,1-3H3/t16-,17+,22-/m0/s1
SMILES	CCO[C@@H]1[C@H](Cc2ccc(c(c2)OC)O)[C@@H](Cc2ccc(c(c2)OC)O)CO1

Calculated Properties

Physi-Chem Properties

Molecular Weight:	388.19	Volume:	400.321 ? Van der Waals volume.
Dense:	0.97	LogP:	2.116 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.198 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-3.385 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	8.0	Rigid Bonds:	17.0
TPSA:	77.38 ? Topological Polar Surface Area.	H-Bond Acceptor:	6.0
H-Bond Donor:	2.0	Rings:	3.0
Heavy Atoms:	6.0

MedChem Properties

QED Drug-Likeness Score:	0.72	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	3.527	Fsp³:	0.455
MCE-18:	58.5 ? 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:	0
Chelating Alert:	1	PAINS Alert:	0
Colloidal aggregators:	0.323	Fluc inhibitor:	0.061 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.017 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.242 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.29	Promiscuous compounds:	0.315

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.858	MDCK Permeability:	-4.697
Pgp-inhibitor:	0.6	Pgp-substrate:	0.306
PAMPA:	0.016 ? 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):	0.01
20% Bioavailability (F20%):	0.553	30% Bioavailability (F30%):	0.712
50% Bioavailability (F50%):	0.943

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.001	MRP1:	0.898
Plasma Protein Binding (PPB):	89.254%	Volume Distribution (VD):	-0.146
Fu:	13.04% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	1.0
OATP1B3 inhibitor:	0.999	BCRP inhibitor:	0.264
BSEP inhibitor:	0.99

ADMET: Metabolism

CYP1A2-inhibitor:	0.941	CYP1A2-substrate:	0.88
CYP2C19-inhibitor:	1.0	CYP2C19-substrate:	0.98
CYP2C9-inhibitor:	0.287	CYP2C9-substrate:	0.242
CYP2D6-inhibitor:	0.344	CYP2D6-substrate:	0.475
CYP3A4-inhibitor:	1.0	CYP3A4-substrate:	1.0
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	1.0
HLM stability:	0.827 ? 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):

9.127

Half-life (T1/2):

1.612

ADMET: Toxicity

hERG Blockers:	0.297	hERG Blockers (10um):	0.773
Human Hepatotoxicity (H-HT):	0.804	Drug-induced Liver Injury (DILI):	0.957
AMES Toxicity:	0.813	Rat Oral Acute Toxicity:	0.375
Maximum Recommended Daily Dose:	0.668	Skin Sensitization:	0.872
Carcinogencity:	0.158	Eye Corrosion:	0.006
Eye Irritation:	0.962	Respiratory Toxicity:	0.629
Drug-induced Neurotoxicity:	0.468	Ototoxicity:	0.551
Hematotoxicity:	0.309	Drug-induced Nephrotoxicity:	0.711
Genotoxicity:	0.933	RPMI-8226 Immunitoxicity:	0.185
A549 Cytotoxicity:	0.485	Hek293 Cytotoxicity:	0.642
BCF:	1.408 ? 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:	3.9 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.121 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.502 ? 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
NPO12339	Daphne feddei	Species	Thymelaeaceae	Eukaryota	stem bark	Kunming, Yunnan Province, China	n.a.	PMID[18986199]
NPO23754	Solanum aculeatissimum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO12339	Daphne feddei	Species	Thymelaeaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO21329	Ilyonectria destructans	Species	Nectriaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO10211	Pajanelia multijuga	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[COCONUT]
NPO23754	Solanum aculeatissimum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO21329	Ilyonectria destructans	Species	Nectriaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO23754	Solanum aculeatissimum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO10211	Pajanelia multijuga	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[UNPD]
NPO12339	Daphne feddei	Species	Thymelaeaceae	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	1

Activity Type	# Activity
Cell line	1

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	=	91000.0	nM	PMID[18986199]

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 NPC275950 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	17272
0.1-0.2	27791
0.2-0.3	4195
0.3-0.4	435
0.4-0.5	109
0.5-0.6	40
0.6-0.7	8
0.7-0.8	0
0.8-0.85	1
0.85-0.9	0
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.8269	Intermediate Similarity	NPC476345
0.6531	Remote Similarity	NPC31344
0.6531	Remote Similarity	NPC317769
0.6296	Remote Similarity	NPC487680
0.6102	Remote Similarity	NPC101624
0.6102	Remote Similarity	NPC184938
0.6102	Remote Similarity	NPC145144
0.6	Remote Similarity	NPC68779
0.6	Remote Similarity	NPC108598
0.5846	Remote Similarity	NPC604694
0.5833	Remote Similarity	NPC165133
0.5833	Remote Similarity	NPC242885
0.5833	Remote Similarity	NPC95614
0.5833	Remote Similarity	NPC232316
0.5714	Remote Similarity	NPC173308
0.5714	Remote Similarity	NPC181079
0.5593	Remote Similarity	NPC273657
0.5574	Remote Similarity	NPC606339
0.5556	Remote Similarity	NPC278961
0.5556	Remote Similarity	NPC113680
0.5484	Remote Similarity	NPC67247
0.5484	Remote Similarity	NPC610284
0.5424	Remote Similarity	NPC475875
0.541	Remote Similarity	NPC110699
0.541	Remote Similarity	NPC106920
0.541	Remote Similarity	NPC300776
0.541	Remote Similarity	NPC15811
0.541	Remote Similarity	NPC176814
0.541	Remote Similarity	NPC4982
0.541	Remote Similarity	NPC106055
0.541	Remote Similarity	NPC606629
0.5319	Remote Similarity	NPC156840
0.5312	Remote Similarity	NPC487679
0.5312	Remote Similarity	NPC487678
0.5294	Remote Similarity	NPC85488
0.5246	Remote Similarity	NPC187998
0.5246	Remote Similarity	NPC257582
0.5246	Remote Similarity	NPC241522
0.5238	Remote Similarity	NPC485282
0.5238	Remote Similarity	NPC485283
0.5238	Remote Similarity	NPC485281
0.5185	Remote Similarity	NPC56214
0.5185	Remote Similarity	NPC487676
0.5167	Remote Similarity	NPC253481
0.5167	Remote Similarity	NPC253722
0.5091	Remote Similarity	NPC227217
0.5091	Remote Similarity	NPC117780
0.5079	Remote Similarity	NPC486558
0.5075	Remote Similarity	NPC281780

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC275950 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	3258
0.1-0.2	5601
0.2-0.3	284
0.3-0.4	6
0.4-0.5	1
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