NPASS Compound

Natural Product: NPC111655

Natural Product ID	NPC111655
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	3,4-Dimethoxy-2,5-Bis(4-Methoxyphenyl)Phenol
IUPAC Name	3,4-dimethoxy-2,5-bis(4-methoxyphenyl)phenol
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL2289484
PubChem CID	71764479
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0002448] Benzenoids [CHEMONTID:0002279] Benzene and substituted derivatives [CHEMONTID:0002042] Terphenyls [CHEMONTID:0002126] P-terphenyls

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 49 51 0 0 0 0 0 0 0 0999 V2000 -7.8457 0.9097 0.3893 C 0 0 0 0 0 0 0 0 0 0 0 0 -7.1276 -0.1524 -0.2106 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.7356 -0.0505 -0.2235 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.9494 -1.0480 -0.7922 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5731 -0.9780 -0.8213 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.9183 0.1087 -0.2746 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.6927 1.1010 0.2908 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.0691 1.0281 0.3184 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4500 0.2060 -0.2936 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.8157 1.3861 -0.6478 C 0 0 0 0 0 0 0 0 0 0 0 0 0.5764 1.4556 -0.6589 C 0 0 0 0 0 0 0 0 0 0 0 0 1.3395 0.3829 -0.3273 C 0 0 0 0 0 0 0 0 0 0 0 0 2.7772 0.4570 -0.3395 C 0 0 0 0 0 0 0 0 0 0 0 0 3.4444 0.8440 0.8130 C 0 0 0 0 0 0 0 0 0 0 0 0 4.8285 0.9195 0.8148 C 0 0 0 0 0 0 0 0 0 0 0 0 5.5832 0.6162 -0.3153 C 0 0 0 0 0 0 0 0 0 0 0 0 4.9052 0.2297 -1.4643 C 0 0 0 0 0 0 0 0 0 0 0 0 3.5283 0.1567 -1.4592 C 0 0 0 0 0 0 0 0 0 0 0 0 6.9555 0.6822 -0.3422 O 0 0 0 0 0 0 0 0 0 0 0 0 7.7392 1.0571 0.7497 C 0 0 0 0 0 0 0 0 0 0 0 0 0.7113 -0.7965 0.0267 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.6768 -0.8843 0.0434 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.2924 -2.0747 0.4009 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.5905 -2.2687 1.7716 C 0 0 0 0 0 0 0 0 0 0 0 0 1.4509 -1.9195 0.3735 O 0 0 0 0 0 0 0 0 0 0 0 0 1.8530 -2.8697 -0.6003 C 0 0 0 0 0 0 0 0 0 0 0 0 1.1563 2.6511 -1.0182 O 0 0 0 0 0 0 0 0 0 0 0 0 -7.5449 1.9037 -0.0435 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.5928 0.9383 1.4763 H 0 0 0 0 0 0 0 0 0 0 0 0 -8.9306 0.7902 0.3097 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.5012 -1.8871 -1.2121 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9891 -1.7787 -1.2756 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1710 1.9505 0.7176 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.6747 1.8236 0.7708 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.3853 2.2633 -0.9186 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9265 1.0949 1.7289 H 0 0 0 0 0 0 0 0 0 0 0 0 5.3251 1.2233 1.7245 H 0 0 0 0 0 0 0 0 0 0 0 0 5.4855 -0.0052 -2.3387 H 0 0 0 0 0 0 0 0 0 0 0 0 3.0315 -0.1468 -2.3677 H 0 0 0 0 0 0 0 0 0 0 0 0 7.9096 2.1654 0.7728 H 0 0 0 0 0 0 0 0 0 0 0 0 8.7514 0.6060 0.7087 H 0 0 0 0 0 0 0 0 0 0 0 0 7.3156 0.7768 1.7340 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.6409 -2.0097 1.9859 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.3986 -3.3347 2.0063 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9231 -1.6475 2.4034 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4530 -2.6334 -1.5925 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9709 -2.8132 -0.6454 H 0 0 0 0 0 0 0 0 0 0 0 0 1.6055 -3.9048 -0.2889 H 0 0 0 0 0 0 0 0 0 0 0 0 0.8657 3.4759 -0.4739 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 6 9 1 0 9 10 2 0 10 11 1 0 11 12 2 0 12 13 1 0 13 14 2 0 14 15 1 0 15 16 2 0 16 17 1 0 17 18 2 0 16 19 1 0 19 20 1 0 12 21 1 0 21 22 2 0 22 23 1 0 23 24 1 0 21 25 1 0 25 26 1 0 11 27 1 0 8 3 1 0 22 9 1 0 18 13 1 0 1 28 1 0 1 29 1 0 1 30 1 0 4 31 1 0 5 32 1 0 7 33 1 0 8 34 1 0 10 35 1 0 14 36 1 0 15 37 1 0 17 38 1 0 18 39 1 0 20 40 1 0 20 41 1 0 20 42 1 0 24 43 1 0 24 44 1 0 24 45 1 0 26 46 1 0 26 47 1 0 26 48 1 0 27 49 1 0 M END

Standard InCHIKey	PWJWVNUGXDCMKF-UHFFFAOYSA-N
Standard InCHI	InChI=1S/C22H22O5/c1-24-16-9-5-14(6-10-16)18-13-19(23)20(22(27-4)21(18)26-3)15-7-11-17(25-2)12-8-15/h5-13,23H,1-4H3
SMILES	COc1ccc(cc1)c1cc(c(c2ccc(cc2)OC)c(c1OC)OC)O

Calculated Properties

Physi-Chem Properties

Molecular Weight:	366.15	Volume:	383.622 ? Van der Waals volume.
Dense:	0.954	LogP:	3.764 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	3.928 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-4.025 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	6.0	Rigid Bonds:	18.0
TPSA:	57.15 ? Topological Polar Surface Area.	H-Bond Acceptor:	5.0
H-Bond Donor:	1.0	Rings:	3.0
Heavy Atoms:	5.0

MedChem Properties

QED Drug-Likeness Score:	0.682	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	2.019	Fsp³:	0.182
MCE-18:	18.0 ? MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.	Lipinski Rule-of-5:	Rejected
Pfizer Rule:	Accepted	GSK Rule:	Rejected
Golden Triangle Rule:	Rejected	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.938	Fluc inhibitor:	0.638 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.433 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.761 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.406	Promiscuous compounds:	0.644

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.862	MDCK Permeability:	-4.644
Pgp-inhibitor:	0.022	Pgp-substrate:	0.009
PAMPA:	0.915 ? 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):	0.42
20% Bioavailability (F20%):	0.085	30% Bioavailability (F30%):	0.018
50% Bioavailability (F50%):	0.719

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.006	MRP1:	0.937
Plasma Protein Binding (PPB):	80.329%	Volume Distribution (VD):	-0.117
Fu:	13.725% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.806
OATP1B3 inhibitor:	0.993	BCRP inhibitor:	0.023
BSEP inhibitor:	0.513

ADMET: Metabolism

CYP1A2-inhibitor:	0.999	CYP1A2-substrate:	0.968
CYP2C19-inhibitor:	0.955	CYP2C19-substrate:	0.981
CYP2C9-inhibitor:	0.998	CYP2C9-substrate:	0.002
CYP2D6-inhibitor:	1.0	CYP2D6-substrate:	0.632
CYP3A4-inhibitor:	0.879	CYP3A4-substrate:	0.074
CYP2B6-substrate:	0.706	CYP2C8-inhibitor:	1.0
HLM stability:	0.981 ? 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):

6.491

Half-life (T1/2):

0.578

ADMET: Toxicity

hERG Blockers:	0.365	hERG Blockers (10um):	0.689
Human Hepatotoxicity (H-HT):	0.513	Drug-induced Liver Injury (DILI):	0.751
AMES Toxicity:	0.572	Rat Oral Acute Toxicity:	0.327
Maximum Recommended Daily Dose:	0.524	Skin Sensitization:	0.225
Carcinogencity:	0.73	Eye Corrosion:	0.009
Eye Irritation:	0.824	Respiratory Toxicity:	0.877
Drug-induced Neurotoxicity:	0.668	Ototoxicity:	0.399
Hematotoxicity:	0.405	Drug-induced Nephrotoxicity:	0.627
Genotoxicity:	0.095	RPMI-8226 Immunitoxicity:	0.188
A549 Cytotoxicity:	0.42	Hek293 Cytotoxicity:	0.63
BCF:	1.723 ? 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:	4.423 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.933 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	5.313 ? 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
NPO33384	Nocardiopsis gilva YIM 90087	Species	Nocardiopsaceae	Bacteria	n.a.	n.a.	n.a.	PMID[23441911]
NPO40966	Nocardiopsis sp. OUCMDZ-4936	Strain	Nocardiopsaceae	Bacteria	n.a.	n.a.	n.a.	PMID[31820976]

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
Activity	2
MIC	5
IC50	25

Activity Type	# Activity
Cell line	25
Others	1
Organism	5
Non-molecular	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
NPT465	Cell line	NCI-N87	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT2276	Cell line	A673	Homo sapiens	IC50	=	8900.0	nM	PMID[31820976]
NPT1649	Cell line	MV4-11	Homo sapiens	IC50	=	770.0	nM	PMID[31820976]
NPT111	Cell line	K562	Homo sapiens	IC50	=	8900.0	nM	PMID[31820976]
NPT81	Cell line	A549	Homo sapiens	IC50	=	9700.0	nM	PMID[31820976]
NPT845	Cell line	BT-474	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT2410	Cell line	NCI-H1299	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT2447	Cell line	HuCCT-1	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT169	Cell line	B16-F10	Mus musculus	IC50	>	100000.0	nM	PMID[31820976]
NPT784	Cell line	MDA-MB-468	Homo sapiens	IC50	=	670.0	nM	PMID[31820976]
NPT2341	Cell line	NCI-H1975	Homo sapiens	IC50	=	4400.0	nM	PMID[31820976]
NPT116	Cell line	HL-60	Homo sapiens	IC50	=	5000.0	nM	PMID[31820976]
NPT762	Cell line	A-431	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT380	Cell line	U-251	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT2427	Cell line	HCC1954	Homo sapiens	IC50	=	2000.0	nM	PMID[31820976]
NPT83	Cell line	MCF7	Homo sapiens	IC50	=	17000.0	nM	PMID[31820976]
NPT1097	Cell line	MKN-45	Homo sapiens	IC50	=	12000.0	nM	PMID[31820976]
NPT90	Cell line	DU-145	Homo sapiens	IC50	=	1000.0	nM	PMID[31820976]
NPT393	Cell line	HCT-116	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT3792	Cell line	143B	Homo sapiens	IC50	=	7700.0	nM	PMID[31820976]
NPT2411	Cell line	NCI-H2228	Homo sapiens	IC50	=	5000.0	nM	PMID[31820976]
NPT82	Cell line	MDA-MB-231	Homo sapiens	IC50	=	2000.0	nM	PMID[31820976]
NPT2067	Cell line	KARPAS-299	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT1535	Cell line	U-87 MG	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT1278	Organism	Fusarium culmorum	Fusarium culmorum	MIC	=	128.0	ug.mL-1	PMID[25437304]
NPT79	Organism	Bacillus subtilis	Bacillus subtilis	MIC	=	64.0	ug.mL-1	PMID[18450455]
NPT20	Organism	Candida albicans	Candida albicans	MIC	=	32.0	ug.mL-1	PMID[23558238]
NPT20529	Non-molecular	NON-PROTEIN TARGET	n.a.	Activity	=	68.6	%	PMID[23441911]
NPT20904	Cell line	Hep 3B2	Homo sapiens	IC50	>	100000.0	nM	PMID[31820976]
NPT1	Others	Radical scavenging activity	n.a.	Activity	=	54.9	%	PMID[18450455]
NPT3660	Organism	Fusarium avenaceum	Fusarium avenaceum	MIC	=	8.0	ug.mL-1	PMID[20705370]
NPT1276	Organism	Gibberella zeae	Gibberella zeae	MIC	=	16.0	ug.mL-1	PMID[20392109]

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 NPC111655 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	28216
0.1-0.2	19251
0.2-0.3	2303
0.3-0.4	76
0.4-0.5	8
0.5-0.6	1
0.6-0.7	2
0.7-0.8	0
0.8-0.85	0
0.85-0.9	1
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.8889	High Similarity	NPC482510
0.6571	Remote Similarity	NPC483135
0.6	Remote Similarity	NPC487129
0.5106	Remote Similarity	NPC482513

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC111655 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	5853
0.1-0.2	3240
0.2-0.3	55
0.3-0.4	2
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