NPASS Compound

Natural Product: NPC474139

Natural Product ID	NPC474139
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	2'-Methoxykobusin
IUPAC Name	5-[(3S,3aR,6S,6aR)-3-(3,4-dimethoxyphenyl)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]furan-6-yl]-4-methyl-1,3-benzodioxole
Synonyms	2'-Methoxykobusin
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL462821
PubChem CID	11025425
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0001392] Lignans, neolignans and related compounds [CHEMONTID:0003686] Furanoid lignans

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 56 0 0 0 0 0 0 0 0999 V2000 6.0396 -2.2522 0.9129 C 0 0 0 0 0 0 0 0 0 0 0 0 6.0899 -0.8615 0.7293 O 0 0 0 0 0 0 0 0 0 0 0 0 4.9294 -0.1958 0.3796 C 0 0 0 0 0 0 0 0 0 0 0 0 3.7065 -0.8517 0.2010 C 0 0 0 0 0 0 0 0 0 0 0 0 2.5729 -0.1626 -0.1461 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6615 1.1979 -0.3168 C 0 0 0 0 0 0 0 0 0 0 0 0 3.8742 1.8743 -0.1433 C 0 0 0 0 0 0 0 0 0 0 0 0 5.0110 1.1772 0.2055 C 0 0 0 0 0 0 0 0 0 0 0 0 6.2335 1.8329 0.3841 O 0 0 0 0 0 0 0 0 0 0 0 0 6.2509 3.2322 0.1922 C 0 0 0 0 0 0 0 0 0 0 0 0 1.3081 -0.8542 -0.3290 C 0 0 1 0 0 0 0 0 0 0 0 0 1.0229 -1.7846 0.6698 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.2597 -2.1984 0.3076 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.9899 -0.8838 0.1978 C 0 0 1 0 0 0 0 0 0 0 0 0 0.0998 0.0228 -0.3122 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.3282 0.3388 -1.6985 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.7004 0.1616 -1.7542 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.0186 -0.8744 -0.8961 C 0 0 2 0 0 0 0 0 0 0 0 0 -3.4091 -0.7748 -0.3802 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.1270 -1.9204 -0.0865 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.4198 -1.8768 0.3942 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.0545 -0.6716 0.6032 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.3581 0.4788 0.3173 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.0499 0.4311 -0.1690 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.3035 1.6675 -0.4755 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.2173 1.5286 0.6135 O 0 0 0 0 0 0 0 0 0 0 0 0 -7.5527 1.0656 0.7316 C 0 0 0 0 0 0 0 0 0 0 0 0 -7.3264 -0.3042 1.0687 O 0 0 0 0 0 0 0 0 0 0 0 0 6.9669 -2.6625 1.3573 H 0 0 0 0 0 0 0 0 0 0 0 0 5.9033 -2.7146 -0.0988 H 0 0 0 0 0 0 0 0 0 0 0 0 5.1909 -2.4748 1.5935 H 0 0 0 0 0 0 0 0 0 0 0 0 3.6797 -1.9080 0.3429 H 0 0 0 0 0 0 0 0 0 0 0 0 1.8178 1.8192 -0.5903 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9089 2.9553 -0.2869 H 0 0 0 0 0 0 0 0 0 0 0 0 5.5732 3.7584 0.9041 H 0 0 0 0 0 0 0 0 0 0 0 0 7.2843 3.6215 0.2660 H 0 0 0 0 0 0 0 0 0 0 0 0 5.8411 3.4310 -0.8193 H 0 0 0 0 0 0 0 0 0 0 0 0 1.3193 -1.4404 -1.2901 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7141 -2.8847 1.0381 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.1545 -2.6801 -0.7028 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.3776 -0.5992 1.1778 H 0 0 0 0 0 0 0 0 0 0 0 0 0.1730 0.8868 0.3616 H 0 0 0 0 0 0 0 0 0 0 0 0 0.1358 -0.3737 -2.4064 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.1121 1.3796 -2.0131 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.8928 -1.8223 -1.4733 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.6553 -2.8921 -0.2400 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.9815 -2.7750 0.6241 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.8630 2.5173 -0.0233 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3057 1.8866 -1.5832 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2960 1.6893 -0.0512 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.9867 1.1411 -0.3067 H 0 0 0 0 0 0 0 0 0 0 0 0 -8.1401 1.5986 1.4779 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 1 0 14 15 1 0 15 16 1 0 16 17 1 0 17 18 1 0 18 19 1 0 19 20 2 0 20 21 1 0 21 22 2 0 22 23 1 0 23 24 2 0 24 25 1 0 23 26 1 0 26 27 1 0 27 28 1 0 8 3 1 0 15 11 1 0 24 19 1 0 18 14 1 0 28 22 1 0 1 29 1 0 1 30 1 0 1 31 1 0 4 32 1 0 6 33 1 0 7 34 1 0 10 35 1 0 10 36 1 0 10 37 1 0 11 38 1 6 13 39 1 0 13 40 1 0 14 41 1 1 15 42 1 1 16 43 1 0 16 44 1 0 18 45 1 6 20 46 1 0 21 47 1 0 25 48 1 0 25 49 1 0 25 50 1 0 27 51 1 0 27 52 1 0 M END

Standard InCHIKey	MPPQCCFNXBGKFC-RZTYQLBFSA-N
Standard InCHI	InChI=1S/C22H24O6/c1-12-14(5-7-18-20(12)28-11-27-18)22-16-10-25-21(15(16)9-26-22)13-4-6-17(23-2)19(8-13)24-3/h4-8,15-16,21-22H,9-11H2,1-3H3/t15-,16-,21+,22+/m0/s1
SMILES	COc1cc(ccc1OC)[C@H]1OC[C@H]2[C@@H]1CO[C@@H]2c1ccc2c(c1C)OCO2

Calculated Properties

Physi-Chem Properties

Molecular Weight:	384.16	Volume:	383.208 ? Van der Waals volume.
Dense:	1.002	LogP:	2.525 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.572 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-3.775 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	4.0	Rigid Bonds:	25.0
TPSA:	55.38 ? Topological Polar Surface Area.	H-Bond Acceptor:	6.0
H-Bond Donor:	0.0	Rings:	5.0
Heavy Atoms:	6.0

MedChem Properties

QED Drug-Likeness Score:	0.799	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	3.879	Fsp³:	0.455
MCE-18:	89.375 ? 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:	0	PAINS Alert:	0
Colloidal aggregators:	0.519	Fluc inhibitor:	0.776 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.062 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.062 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.211	Promiscuous compounds:	0.17

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.948	MDCK Permeability:	-4.754
Pgp-inhibitor:	0.735	Pgp-substrate:	0.04
PAMPA:	0.002 ? 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):	0.0
20% Bioavailability (F20%):	0.008	30% Bioavailability (F30%):	0.001
50% Bioavailability (F50%):	0.301

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.903	MRP1:	0.971
Plasma Protein Binding (PPB):	96.54%	Volume Distribution (VD):	0.101
Fu:	3.815% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.957
OATP1B3 inhibitor:	0.954	BCRP inhibitor:	0.085
BSEP inhibitor:	0.998

ADMET: Metabolism

CYP1A2-inhibitor:	1.0	CYP1A2-substrate:	0.989
CYP2C19-inhibitor:	1.0	CYP2C19-substrate:	0.702
CYP2C9-inhibitor:	0.838	CYP2C9-substrate:	0.968
CYP2D6-inhibitor:	0.994	CYP2D6-substrate:	1.0
CYP3A4-inhibitor:	1.0	CYP3A4-substrate:	1.0
CYP2B6-substrate:	0.01	CYP2C8-inhibitor:	0.002
HLM stability:	0.752 ? 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):

7.436

Half-life (T1/2):

1.548

ADMET: Toxicity

hERG Blockers:	0.125	hERG Blockers (10um):	0.407
Human Hepatotoxicity (H-HT):	0.741	Drug-induced Liver Injury (DILI):	0.941
AMES Toxicity:	0.817	Rat Oral Acute Toxicity:	0.309
Maximum Recommended Daily Dose:	0.296	Skin Sensitization:	0.855
Carcinogencity:	0.791	Eye Corrosion:	0.033
Eye Irritation:	0.949	Respiratory Toxicity:	0.432
Drug-induced Neurotoxicity:	0.546	Ototoxicity:	0.309
Hematotoxicity:	0.554	Drug-induced Nephrotoxicity:	0.691
Genotoxicity:	0.711	RPMI-8226 Immunitoxicity:	0.155
A549 Cytotoxicity:	0.174	Hek293 Cytotoxicity:	0.316
BCF:	2.171 ? 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:	4.07 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.781 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	5.046 ? 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
NPO11997	Leucophyllum ambiguum	Species	Scrophulariaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[12608853]
NPO11997	Leucophyllum ambiguum	Species	Scrophulariaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[32239935]
NPO11997	Leucophyllum ambiguum	Species	Scrophulariaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO11997	Leucophyllum ambiguum	Species	Scrophulariaceae	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
Others	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
NPT2	Others	Unspecified	n.a.	IC50	=	14400.0	nM	PMID[19916528]

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 NPC474139 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	29765
0.1-0.2	18232
0.2-0.3	1554
0.3-0.4	196
0.4-0.5	69
0.5-0.6	21
0.6-0.7	14
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
0.7551	Intermediate Similarity	NPC227160
0.7551	Intermediate Similarity	NPC82111
0.7414	Intermediate Similarity	NPC265154
0.6809	Remote Similarity	NPC121783
0.6809	Remote Similarity	NPC34902
0.6809	Remote Similarity	NPC18449
0.6735	Remote Similarity	NPC171928
0.6735	Remote Similarity	NPC158526
0.6735	Remote Similarity	NPC129687
0.6735	Remote Similarity	NPC33611
0.6735	Remote Similarity	NPC16830
0.6735	Remote Similarity	NPC100223
0.6604	Remote Similarity	NPC189474
0.6275	Remote Similarity	NPC222127
0.6275	Remote Similarity	NPC82862
0.6034	Remote Similarity	NPC298317
0.6034	Remote Similarity	NPC255566
0.5932	Remote Similarity	NPC483653
0.5849	Remote Similarity	NPC606146
0.5833	Remote Similarity	NPC88640
0.5833	Remote Similarity	NPC101153
0.5833	Remote Similarity	NPC193666
0.5833	Remote Similarity	NPC123526
0.5833	Remote Similarity	NPC608725
0.566	Remote Similarity	NPC148893
0.566	Remote Similarity	NPC25333
0.566	Remote Similarity	NPC49235
0.5517	Remote Similarity	NPC27843
0.5517	Remote Similarity	NPC7171
0.5455	Remote Similarity	NPC312199
0.5273	Remote Similarity	NPC57119
0.5273	Remote Similarity	NPC158471
0.5273	Remote Similarity	NPC226862
0.5263	Remote Similarity	NPC488505
0.5254	Remote Similarity	NPC14022
0.5254	Remote Similarity	NPC601703
0.5088	Remote Similarity	NPC483654
0.5082	Remote Similarity	NPC469981

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC474139 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	5162
0.1-0.2	3860
0.2-0.3	126
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