NPASS Compound

Natural Product: NPC229401

Natural Product ID	NPC229401
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	4-[(E)-3-Hydroxyprop-1-Enyl]-2,6-Dimethoxyphenol
IUPAC Name	4-[(E)-3-hydroxyprop-1-enyl]-2,6-dimethoxyphenol
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL1800816
PubChem CID	5280507
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0002448] Benzenoids [CHEMONTID:0000134] Phenols [CHEMONTID:0000190] Methoxyphenols

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 29 29 0 0 0 0 0 0 0 0999 V2000 -1.8275 -3.6460 -0.6440 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.5164 -2.4326 -0.4328 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.7604 -1.2850 -0.2311 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3838 -1.2988 -0.2316 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3784 -0.1684 -0.0329 C 0 0 0 0 0 0 0 0 0 0 0 0 1.8390 -0.2675 -0.0482 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6551 0.7403 0.1291 C 0 0 0 0 0 0 0 0 0 0 0 0 4.1218 0.4923 0.0878 C 0 0 0 0 0 0 0 0 0 0 0 0 4.7365 0.8444 1.2948 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.3077 1.0055 0.1714 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.6863 1.0675 0.1804 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4172 -0.0835 -0.0219 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.8032 -0.0671 -0.0209 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.3821 2.2504 0.3863 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.6720 3.4476 0.5966 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0795 -3.8089 0.1447 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.3621 -3.7058 -1.6544 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.6156 -4.4504 -0.6283 H 0 0 0 0 0 0 0 0 0 0 0 0 0.1098 -2.2422 -0.3960 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2924 -1.2571 -0.2207 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2422 1.7260 0.3010 H 0 0 0 0 0 0 0 0 0 0 0 0 4.6149 1.0633 -0.7116 H 0 0 0 0 0 0 0 0 0 0 0 0 4.3260 -0.5790 -0.0997 H 0 0 0 0 0 0 0 0 0 0 0 0 5.0113 0.0226 1.7945 H 0 0 0 0 0 0 0 0 0 0 0 0 0.2333 1.9147 0.3312 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.2939 -0.6447 -0.6720 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9588 3.6871 -0.2121 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4091 4.2859 0.7431 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.0849 3.3898 1.5501 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 2 3 1 0 3 4 2 0 4 5 1 0 5 6 1 0 6 7 2 0 7 8 1 0 8 9 1 0 5 10 2 0 10 11 1 0 11 12 2 0 12 13 1 0 11 14 1 0 14 15 1 0 12 3 1 0 1 16 1 0 1 17 1 0 1 18 1 0 4 19 1 0 6 20 1 0 7 21 1 0 8 22 1 0 8 23 1 0 9 24 1 0 10 25 1 0 13 26 1 0 15 27 1 0 15 28 1 0 15 29 1 0 M END

Standard InCHIKey	LZFOPEXOUVTGJS-ONEGZZNKSA-N
Standard InCHI	InChI=1S/C11H14O4/c1-14-9-6-8(4-3-5-12)7-10(15-2)11(9)13/h3-4,6-7,12-13H,5H2,1-2H3/b4-3+
SMILES	COc1cc(/C=C/CO)cc(c1O)OC

Calculated Properties

Physi-Chem Properties

Molecular Weight:	210.09	Volume:	214.871 ? Van der Waals volume.
Dense:	0.978	LogP:	1.229 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	1.368 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-1.93 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	4.0	Rigid Bonds:	7.0
TPSA:	58.92 ? 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:	0.789	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	2.172	Fsp³:	0.273
MCE-18:	7.0 ? 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:	0.109	Fluc inhibitor:	0.682 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.033 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.289 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.846	Promiscuous compounds:	0.53

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.069	MDCK Permeability:	-4.772
Pgp-inhibitor:	0.372	Pgp-substrate:	0.217
PAMPA:	0.036 ? 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):	0.077
20% Bioavailability (F20%):	0.47	30% Bioavailability (F30%):	0.607
50% Bioavailability (F50%):	0.891

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.116	MRP1:	0.715
Plasma Protein Binding (PPB):	74.446%	Volume Distribution (VD):	-0.396
Fu:	23.733% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.975
OATP1B3 inhibitor:	0.987	BCRP inhibitor:	0.838
BSEP inhibitor:	0.791

ADMET: Metabolism

CYP1A2-inhibitor:	0.017	CYP1A2-substrate:	0.038
CYP2C19-inhibitor:	0.527	CYP2C19-substrate:	0.262
CYP2C9-inhibitor:	0.7	CYP2C9-substrate:	0.201
CYP2D6-inhibitor:	0.906	CYP2D6-substrate:	0.018
CYP3A4-inhibitor:	0.015	CYP3A4-substrate:	0.021
CYP2B6-substrate:	0.004	CYP2C8-inhibitor:	0.528
HLM stability:	0.846 ? 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):

9.2

Half-life (T1/2):

1.502

ADMET: Toxicity

hERG Blockers:	0.13	hERG Blockers (10um):	0.395
Human Hepatotoxicity (H-HT):	0.674	Drug-induced Liver Injury (DILI):	0.393
AMES Toxicity:	0.441	Rat Oral Acute Toxicity:	0.098
Maximum Recommended Daily Dose:	0.31	Skin Sensitization:	0.737
Carcinogencity:	0.514	Eye Corrosion:	0.285
Eye Irritation:	0.985	Respiratory Toxicity:	0.65
Drug-induced Neurotoxicity:	0.52	Ototoxicity:	0.254
Hematotoxicity:	0.215	Drug-induced Nephrotoxicity:	0.228
Genotoxicity:	0.148	RPMI-8226 Immunitoxicity:	0.091
A549 Cytotoxicity:	0.126	Hek293 Cytotoxicity:	0.212
BCF:	0.376 ? 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:	2.733 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.183 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	3.373 ? 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
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	fruits	n.a.	n.a.	PMID[17625893]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	Fruits	n.a.	n.a.	PMID[18293924]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[20192247]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	n.a.	fruit	n.a.	PMID[21319773]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	fruits	n.a.	n.a.	PMID[22445674]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	fruits	n.a.	n.a.	PMID[23623680]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	fruits	n.a.	n.a.	PMID[25735399]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	Fruits	n.a.	n.a.	PMID[28322565]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	Fruits	n.a.	n.a.	PMID[28968119]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO16066	Urtica cannabina	Species	Urticaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO16066	Urtica cannabina	Species	Urticaceae	Eukaryota	n.a.	n.a.	n.a.	Database[HerDing]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	n.a.	n.a.	n.a.	Database[HerDing]
NPO16066	Urtica cannabina	Species	Urticaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCM_Taiwan]
NPO16066	Urtica cannabina	Species	Urticaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCM_Taiwan]
NPO16066	Urtica cannabina	Species	Urticaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO22079	Paulownia tomentosa	Species	Paulowniaceae	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	6

Activity Type	# Activity
Cell line	4
Non-molecular	2

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
NPT81	Cell line	A549	Homo sapiens	IC50	>	100000.0	nM	PMID[21696954]
NPT306	Cell line	PC-3	Homo sapiens	IC50	>	100000.0	nM	PMID[21696954]
NPT170	Cell line	SK-MEL-28	Homo sapiens	IC50	>	100000.0	nM	PMID[21696954]
NPT114	Cell line	LoVo	Homo sapiens	IC50	>	100000.0	nM	PMID[21696954]
NPT20529	Non-molecular	NON-PROTEIN TARGET	n.a.	IC50	>	100000.0	nM	PMID[21696954]
NPT20529	Non-molecular	NON-PROTEIN TARGET	n.a.	IC50	=	80000.0	nM	PMID[21696954]

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 NPC229401 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	24107
0.1-0.2	20292
0.2-0.3	4918
0.3-0.4	460
0.4-0.5	57
0.5-0.6	11
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
0.6944	Remote Similarity	NPC78918
0.6944	Remote Similarity	NPC139617
0.6765	Remote Similarity	NPC271985
0.6216	Remote Similarity	NPC58279
0.6	Remote Similarity	NPC184447
0.5952	Remote Similarity	NPC48315
0.5714	Remote Similarity	NPC4718
0.5676	Remote Similarity	NPC227894
0.5625	Remote Similarity	NPC170694
0.561	Remote Similarity	NPC200014
0.561	Remote Similarity	NPC109275
0.5385	Remote Similarity	NPC300326
0.5312	Remote Similarity	NPC193067
0.5238	Remote Similarity	NPC483673
0.52	Remote Similarity	NPC87725
0.52	Remote Similarity	NPC263261

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC229401 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	4853
0.1-0.2	4160
0.2-0.3	127
0.3-0.4	9
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