NPASS Compound

Natural Product: NPC134677

Natural Product ID	NPC134677
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Natsudaidai
IUPAC Name	2-(3,4-dimethoxyphenyl)-3-hydroxy-5,6,7,8-tetramethoxychromen-4-one
Synonyms	3-hydroxynobiletin
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL225702
PubChem CID	3084605
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000261] Phenylpropanoids and polyketides [CHEMONTID:0000334] Flavonoids [CHEMONTID:0001615] Flavones [CHEMONTID:0001136] Flavonols

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 52 54 0 0 0 0 0 0 0 0999 V2000 5.6566 2.4917 -0.7844 C 0 0 0 0 0 0 0 0 0 0 0 0 5.8564 1.1497 -0.4499 O 0 0 0 0 0 0 0 0 0 0 0 0 4.7448 0.3464 -0.2238 C 0 0 0 0 0 0 0 0 0 0 0 0 3.4434 0.8588 -0.3258 C 0 0 0 0 0 0 0 0 0 0 0 0 2.3733 0.0610 -0.1021 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6360 -1.2740 0.2293 C 0 0 0 0 0 0 0 0 0 0 0 0 3.9009 -1.7693 0.3278 C 0 0 0 0 0 0 0 0 0 0 0 0 4.9882 -0.9707 0.1034 C 0 0 0 0 0 0 0 0 0 0 0 0 6.2723 -1.4461 0.1965 O 0 0 0 0 0 0 0 0 0 0 0 0 6.5700 -2.7722 0.5249 C 0 0 0 0 0 0 0 0 0 0 0 0 0.9953 0.4828 -0.1795 C 0 0 0 0 0 0 0 0 0 0 0 0 0.0544 -0.4348 0.0717 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.2145 -0.1833 0.0349 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.1199 -1.1831 0.3061 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.6603 -2.4508 0.6162 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.4404 -3.4226 -0.3975 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4612 -0.9051 0.2641 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.3639 -1.9279 0.5410 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.8310 -2.7275 -0.5067 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.9214 0.3786 -0.0501 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.0219 1.3855 -0.3229 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.6735 1.0948 -0.2779 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7431 2.0657 -0.5423 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0521 3.2500 -0.8346 O 0 0 0 0 0 0 0 0 0 0 0 0 0.6187 1.7581 -0.4933 C 0 0 0 0 0 0 0 0 0 0 0 0 1.5404 2.7791 -0.7702 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.4485 2.6589 -0.6352 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.6712 3.6734 0.2952 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.3004 0.6311 -0.0848 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.9965 1.0576 1.0649 C 0 0 0 0 0 0 0 0 0 0 0 0 5.0204 2.5252 -1.6869 H 0 0 0 0 0 0 0 0 0 0 0 0 5.1299 3.0621 0.0172 H 0 0 0 0 0 0 0 0 0 0 0 0 6.6236 3.0146 -0.9353 H 0 0 0 0 0 0 0 0 0 0 0 0 3.4028 1.8935 -0.5861 H 0 0 0 0 0 0 0 0 0 0 0 0 1.8232 -1.9851 0.4258 H 0 0 0 0 0 0 0 0 0 0 0 0 4.0643 -2.8097 0.5869 H 0 0 0 0 0 0 0 0 0 0 0 0 6.2988 -3.4166 -0.3570 H 0 0 0 0 0 0 0 0 0 0 0 0 7.6612 -2.8972 0.6532 H 0 0 0 0 0 0 0 0 0 0 0 0 5.9771 -3.1394 1.3830 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.3404 -2.9615 -1.3804 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2964 -4.1491 -0.4512 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5484 -4.0484 -0.1597 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.9047 -2.5250 -0.7182 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7826 -3.8013 -0.1637 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.2758 -2.6204 -1.4457 H 0 0 0 0 0 0 0 0 0 0 0 0 1.2769 3.7430 -0.6646 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1393 3.4708 1.2401 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7764 3.8081 0.4520 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3084 4.6690 -0.0576 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.3482 1.0199 1.9632 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.8911 0.4095 1.2065 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.3978 2.0823 0.8755 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 2 0 6 7 1 0 7 8 2 0 8 9 1 0 9 10 1 0 5 11 1 0 11 12 1 0 12 13 1 0 13 14 2 0 14 15 1 0 15 16 1 0 14 17 1 0 17 18 1 0 18 19 1 0 17 20 2 0 20 21 1 0 21 22 2 0 22 23 1 0 23 24 2 0 23 25 1 0 25 26 1 0 21 27 1 0 27 28 1 0 20 29 1 0 29 30 1 0 8 3 1 0 25 11 2 0 22 13 1 0 1 31 1 0 1 32 1 0 1 33 1 0 4 34 1 0 6 35 1 0 7 36 1 0 10 37 1 0 10 38 1 0 10 39 1 0 16 40 1 0 16 41 1 0 16 42 1 0 19 43 1 0 19 44 1 0 19 45 1 0 26 46 1 0 28 47 1 0 28 48 1 0 28 49 1 0 30 50 1 0 30 51 1 0 30 52 1 0 M END

Standard InCHIKey	CCJBNIRSVUKABH-UHFFFAOYSA-N
Standard InCHI	InChI=1S/C21H22O9/c1-24-11-8-7-10(9-12(11)25-2)16-15(23)14(22)13-17(26-3)19(27-4)21(29-6)20(28-5)18(13)30-16/h7-9,23H,1-6H3
SMILES	COc1cc(ccc1OC)c1oc2c(OC)c(OC)c(c(c2c(=O)c1O)OC)OC

Calculated Properties

Physi-Chem Properties

Molecular Weight:	418.13	Volume:	404.123 ? Van der Waals volume.
Dense:	1.035	LogP:	1.675 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	1.953 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-2.91 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	7.0	Rigid Bonds:	18.0
TPSA:	105.82 ? Topological Polar Surface Area.	H-Bond Acceptor:	9.0
H-Bond Donor:	1.0	Rings:	3.0
Heavy Atoms:	9.0

MedChem Properties

QED Drug-Likeness Score:	0.619	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	2.57	Fsp³:	0.286
MCE-18:	21.0 ? 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:	Accepted
Golden Triangle Rule:	Rejected	BMS Rule:	0
Chelating Alert:	1	PAINS Alert:	0
Colloidal aggregators:	0.09	Fluc inhibitor:	0.564 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.839 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.749 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.306	Promiscuous compounds:	0.35

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.06	MDCK Permeability:	-4.699
Pgp-inhibitor:	0.968	Pgp-substrate:	0.03
PAMPA:	0.017 ? 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):	0.292
20% Bioavailability (F20%):	0.051	30% Bioavailability (F30%):	0.134
50% Bioavailability (F50%):	0.859

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.005	MRP1:	0.866
Plasma Protein Binding (PPB):	94.521%	Volume Distribution (VD):	-0.422
Fu:	4.657% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.896
OATP1B3 inhibitor:	0.999	BCRP inhibitor:	0.989
BSEP inhibitor:	0.995

ADMET: Metabolism

CYP1A2-inhibitor:	0.956	CYP1A2-substrate:	0.007
CYP2C19-inhibitor:	0.888	CYP2C19-substrate:	0.578
CYP2C9-inhibitor:	0.32	CYP2C9-substrate:	0.0
CYP2D6-inhibitor:	0.969	CYP2D6-substrate:	0.435
CYP3A4-inhibitor:	1.0	CYP3A4-substrate:	0.207
CYP2B6-substrate:	0.037	CYP2C8-inhibitor:	0.503
HLM stability:	0.429 ? 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):

6.436

Half-life (T1/2):

1.662

ADMET: Toxicity

hERG Blockers:	0.124	hERG Blockers (10um):	0.531
Human Hepatotoxicity (H-HT):	0.461	Drug-induced Liver Injury (DILI):	0.789
AMES Toxicity:	0.281	Rat Oral Acute Toxicity:	0.356
Maximum Recommended Daily Dose:	0.264	Skin Sensitization:	0.593
Carcinogencity:	0.768	Eye Corrosion:	0.379
Eye Irritation:	0.834	Respiratory Toxicity:	0.662
Drug-induced Neurotoxicity:	0.576	Ototoxicity:	0.242
Hematotoxicity:	0.571	Drug-induced Nephrotoxicity:	0.294
Genotoxicity:	0.064	RPMI-8226 Immunitoxicity:	0.144
A549 Cytotoxicity:	0.141	Hek293 Cytotoxicity:	0.313
BCF:	1.589 ? 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:	3.677 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.901 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.031 ? 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
NPO19584	Pericarpium citri reticulatae	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[COCONUT]
NPO27662	Pericarpium citri reticulatae viride	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[COCONUT]
NPO19584	Pericarpium citri reticulatae	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[TCMID]
NPO27662	Pericarpium citri reticulatae viride	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[TCMID]

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
AC50	1

Activity Type	# Activity
Cell line	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
NPT116	Cell line	HL-60	Homo sapiens	IC50	>	100000.0	nM	PMID[17391969]
NPT116	Cell line	HL-60	Homo sapiens	AC50	=	56510.0	nM	PMID[17391969]

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 NPC134677 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	27204
0.1-0.2	19566
0.2-0.3	2574
0.3-0.4	391
0.4-0.5	88
0.5-0.6	25
0.6-0.7	4
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
0.7143	Intermediate Similarity	NPC224137
0.6667	Remote Similarity	NPC201547
0.6545	Remote Similarity	NPC85233
0.6379	Remote Similarity	NPC50728
0.6271	Remote Similarity	NPC261548
0.5833	Remote Similarity	NPC159103
0.5833	Remote Similarity	NPC166753
0.5833	Remote Similarity	NPC602344
0.5738	Remote Similarity	NPC75215
0.5738	Remote Similarity	NPC2476
0.5574	Remote Similarity	NPC257914
0.5484	Remote Similarity	NPC189179
0.5484	Remote Similarity	NPC7846
0.541	Remote Similarity	NPC50715
0.541	Remote Similarity	NPC86485
0.5323	Remote Similarity	NPC255350
0.5263	Remote Similarity	NPC283002
0.5246	Remote Similarity	NPC608038
0.5238	Remote Similarity	NPC474520
0.5172	Remote Similarity	NPC40818
0.5167	Remote Similarity	NPC226973
0.5167	Remote Similarity	NPC259058
0.5082	Remote Similarity	NPC110639
0.5082	Remote Similarity	NPC205522
0.5082	Remote Similarity	NPC215932
0.5082	Remote Similarity	NPC138360
0.5079	Remote Similarity	NPC115798
0.5079	Remote Similarity	NPC167815
0.5079	Remote Similarity	NPC183597
0.5079	Remote Similarity	NPC178854

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC134677 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	4855
0.1-0.2	4213
0.2-0.3	77
0.3-0.4	3
0.4-0.5	1
0.5-0.6	1
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
0.5323	Remote Similarity	NPD2801	Pre-clinical

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