NPASS Compound

Natural Product: NPC474936

Natural Product ID	NPC474936
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	6-O-3',4'-Dimethoxybenzoyl Ajugol
IUPAC Name	[(2R,3S,4S,5R,6S)-6-[[(1S,4aR,5R,7S,7aS)-5,7-dihydroxy-7-methyl-4a,5,6,7a-tetrahydro-1H-cyclopenta[c]pyran-1-yl]oxy]-3,4,5-trihydroxyoxan-2-yl]methyl 3,4-dimethoxybenzoate
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL488723
PubChem CID	44575706
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000261] Phenylpropanoids and polyketides [CHEMONTID:0000238] Tannins [CHEMONTID:0001710] Hydrolyzable tannins

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 68 71 0 0 0 0 0 0 0 0999 V2000 7.8498 -0.9839 -2.6851 C 0 0 0 0 0 0 0 0 0 0 0 0 8.1987 -0.6724 -1.3434 O 0 0 0 0 0 0 0 0 0 0 0 0 7.2222 -0.2801 -0.4397 C 0 0 0 0 0 0 0 0 0 0 0 0 5.8817 -0.1743 -0.7929 C 0 0 0 0 0 0 0 0 0 0 0 0 4.9359 0.2162 0.1188 C 0 0 0 0 0 0 0 0 0 0 0 0 5.3159 0.5091 1.4068 C 0 0 0 0 0 0 0 0 0 0 0 0 6.6541 0.4014 1.7512 C 0 0 0 0 0 0 0 0 0 0 0 0 7.6282 0.0084 0.8453 C 0 0 0 0 0 0 0 0 0 0 0 0 8.9648 -0.0954 1.2024 O 0 0 0 0 0 0 0 0 0 0 0 0 9.3224 0.2123 2.5342 C 0 0 0 0 0 0 0 0 0 0 0 0 3.5414 0.3039 -0.3196 C 0 0 0 0 0 0 0 0 0 0 0 0 3.2956 0.0018 -1.5119 O 0 0 0 0 0 0 0 0 0 0 0 0 2.5171 0.6854 0.4694 O 0 0 0 0 0 0 0 0 0 0 0 0 1.1625 0.8177 0.2847 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3022 -0.3966 0.1551 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.9851 0.0406 -0.0651 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.9470 -0.8189 -0.4093 C 0 0 1 0 0 0 0 0 0 0 0 0 -2.9959 -0.0668 -0.9897 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.1672 -0.1133 -0.2886 C 0 0 2 0 0 0 0 0 0 0 0 0 -5.2059 -0.6254 -1.1282 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.4933 0.1410 -2.2439 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.4572 1.4487 -2.1460 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.1222 2.1401 -0.8885 C 0 0 2 0 0 0 0 0 0 0 0 0 -4.5043 1.2836 0.1753 C 0 0 1 0 0 0 0 0 0 0 0 0 -5.5250 1.2652 1.2981 C 0 0 1 0 0 0 0 0 0 0 0 0 -5.6204 -0.0375 2.0139 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.3307 2.3019 2.1910 O 0 0 0 0 0 0 0 0 0 0 0 0 -6.8546 1.4894 0.5644 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.4492 2.6524 -0.3293 C 0 0 1 0 0 0 0 0 0 0 0 0 -6.3021 3.7754 0.4603 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.6128 -1.9832 -1.2742 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.3291 -2.6029 -0.8138 C 0 0 2 0 0 0 0 0 0 0 0 0 0.7593 -1.5391 -0.6296 C 0 0 2 0 0 0 0 0 0 0 0 0 1.8785 -2.1939 -0.0860 O 0 0 0 0 0 0 0 0 0 0 0 0 0.0620 -3.5435 -1.7644 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.6132 -2.9642 -1.0851 O 0 0 0 0 0 0 0 0 0 0 0 0 6.9975 -1.6843 -2.7439 H 0 0 0 0 0 0 0 0 0 0 0 0 8.7335 -1.4747 -3.1363 H 0 0 0 0 0 0 0 0 0 0 0 0 7.6175 -0.0382 -3.2456 H 0 0 0 0 0 0 0 0 0 0 0 0 5.6299 -0.4185 -1.8278 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5781 0.8262 2.1618 H 0 0 0 0 0 0 0 0 0 0 0 0 6.9665 0.6320 2.7697 H 0 0 0 0 0 0 0 0 0 0 0 0 9.0252 1.2458 2.8214 H 0 0 0 0 0 0 0 0 0 0 0 0 8.7362 -0.4603 3.1933 H 0 0 0 0 0 0 0 0 0 0 0 0 10.4247 0.0963 2.6762 H 0 0 0 0 0 0 0 0 0 0 0 0 0.7825 1.4525 1.1523 H 0 0 0 0 0 0 0 0 0 0 0 0 0.9326 1.5172 -0.5958 H 0 0 0 0 0 0 0 0 0 0 0 0 0.2349 -0.8024 1.2429 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4178 -1.2502 0.5243 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.1245 -0.7361 0.6279 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.7498 -0.3505 -3.2021 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.6890 2.0310 -3.0555 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.4999 3.0435 -1.1130 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.5876 1.8211 0.5294 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7062 -0.3350 2.5396 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.0420 -0.8461 1.3687 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.3960 0.0976 2.8200 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.6341 2.1127 3.0960 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.0279 0.5985 -0.0874 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.6697 1.7332 1.2413 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.2033 2.7472 -1.1286 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.9640 3.6985 1.2177 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5039 -1.7347 -2.3451 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.4357 -3.1407 0.1496 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0164 -1.2459 -1.6580 H 0 0 0 0 0 0 0 0 0 0 0 0 1.6802 -2.5924 0.7972 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.3876 -3.4041 -2.6420 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2937 -3.7422 -0.5973 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 2 0 11 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 1 0 20 21 1 0 21 22 2 0 22 23 1 0 23 24 1 0 24 25 1 0 25 26 1 0 25 27 1 1 25 28 1 0 28 29 1 0 29 30 1 0 17 31 1 0 31 32 1 0 32 33 1 0 33 34 1 0 32 35 1 0 31 36 1 0 8 3 1 0 33 15 1 0 24 19 1 0 29 23 1 0 1 37 1 0 1 38 1 0 1 39 1 0 4 40 1 0 6 41 1 0 7 42 1 0 10 43 1 0 10 44 1 0 10 45 1 0 14 46 1 0 14 47 1 0 15 48 1 1 17 49 1 1 19 50 1 1 21 51 1 0 22 52 1 0 23 53 1 6 24 54 1 1 26 55 1 0 26 56 1 0 26 57 1 0 27 58 1 0 28 59 1 0 28 60 1 0 29 61 1 6 30 62 1 0 31 63 1 6 32 64 1 1 33 65 1 6 34 66 1 0 35 67 1 0 36 68 1 0 M END

Standard InCHIKey	MHLBJQVZNLCHBZ-NPWFAMOPSA-N
Standard InCHI	InChI=1S/C24H32O12/c1-24(30)9-13(25)12-6-7-33-22(17(12)24)36-23-20(28)19(27)18(26)16(35-23)10-34-21(29)11-4-5-14(31-2)15(8-11)32-3/h4-8,12-13,16-20,22-23,25-28,30H,9-10H2,1-3H3/t12-,13+,16+,17+,18+,19-,20+,22-,23-,24-/m0/s1
SMILES	COc1cc(ccc1OC)C(=O)OC[C@H]1O[C@@H](O[C@@H]2OC=C[C@@H]3[C@H]2[C@@](C)(O)C[C@H]3O)[C@@H]([C@H]([C@@H]1O)O)O

Calculated Properties

Physi-Chem Properties

Molecular Weight:	512.19	Volume:	481.735 ? Van der Waals volume.
Dense:	1.063	LogP:	1.079 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	1.538 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-2.443 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	8.0	Rigid Bonds:	23.0
TPSA:	173.6 ? Topological Polar Surface Area.	H-Bond Acceptor:	12.0
H-Bond Donor:	5.0	Rings:	4.0
Heavy Atoms:	12.0

MedChem Properties

QED Drug-Likeness Score:	0.291	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	4.699	Fsp³:	0.625
MCE-18:	99.795 ? MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.	Lipinski Rule-of-5:	Accepted
Pfizer Rule:	Rejected	GSK Rule:	Accepted
Golden Triangle Rule:	Accepted	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.394	Fluc inhibitor:	0.202 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.018 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.032 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.101	Promiscuous compounds:	0.231

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.881	MDCK Permeability:	-5.279
Pgp-inhibitor:	0.017	Pgp-substrate:	0.625
PAMPA:	0.946 ? 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):	0.784
20% Bioavailability (F20%):	0.927	30% Bioavailability (F30%):	0.98
50% Bioavailability (F50%):	0.994

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.016	MRP1:	0.727
Plasma Protein Binding (PPB):	49.781%	Volume Distribution (VD):	-0.456
Fu:	49.003% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.991
OATP1B3 inhibitor:	0.999	BCRP inhibitor:	0.044
BSEP inhibitor:	0.558

ADMET: Metabolism

CYP1A2-inhibitor:	0.029	CYP1A2-substrate:	0.0
CYP2C19-inhibitor:	0.001	CYP2C19-substrate:	0.0
CYP2C9-inhibitor:	0.0	CYP2C9-substrate:	0.005
CYP2D6-inhibitor:	0.0	CYP2D6-substrate:	0.005
CYP3A4-inhibitor:	0.033	CYP3A4-substrate:	0.986
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.805
HLM stability:	0.521 ? 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):

1.179

Half-life (T1/2):

2.841

ADMET: Toxicity

hERG Blockers:	0.023	hERG Blockers (10um):	0.437
Human Hepatotoxicity (H-HT):	0.159	Drug-induced Liver Injury (DILI):	0.852
AMES Toxicity:	0.598	Rat Oral Acute Toxicity:	0.032
Maximum Recommended Daily Dose:	0.062	Skin Sensitization:	0.937
Carcinogencity:	0.573	Eye Corrosion:	0.001
Eye Irritation:	0.522	Respiratory Toxicity:	0.031
Drug-induced Neurotoxicity:	0.069	Ototoxicity:	0.725
Hematotoxicity:	0.097	Drug-induced Nephrotoxicity:	0.814
Genotoxicity:	0.098	RPMI-8226 Immunitoxicity:	0.135
A549 Cytotoxicity:	0.056	Hek293 Cytotoxicity:	0.09
BCF:	0.361 ? 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:	3.129 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.875 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	3.974 ? 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
NPO14242	Maytenus laevis	Species	Celastraceae	Eukaryota	bark	Leticia, Colombia	n.a.	PMID[15568791]
NPO14242	Maytenus laevis	Species	Celastraceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO14242	Maytenus laevis	Species	Celastraceae	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
Activity	6

Activity Type	# Activity
Cell line	6

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
NPT927	Cell line	PBMC	Homo sapiens	Activity	=	12.6	pg/ml	PubChem BioAssay data set
NPT927	Cell line	PBMC	Homo sapiens	Activity	=	27.2	pg/ml	PMID[23543830]
NPT927	Cell line	PBMC	Homo sapiens	Activity	=	38.1	pg/ml	PMID[23543830]
NPT927	Cell line	PBMC	Homo sapiens	Activity	=	849.5	pg/ml	PMID[19805556]
NPT927	Cell line	PBMC	Homo sapiens	Activity	<	7.8	pg/ml	PMID[21353545]

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 NPC474936 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	8276
0.1-0.2	37390
0.2-0.3	3871
0.3-0.4	276
0.4-0.5	34
0.5-0.6	9
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	Natural Product ID
0.7949	Intermediate Similarity	NPC476011
0.7195	Intermediate Similarity	NPC308178
0.5667	Remote Similarity	NPC282551
0.5479	Remote Similarity	NPC259296
0.5479	Remote Similarity	NPC98276
0.5349	Remote Similarity	NPC470683
0.5349	Remote Similarity	NPC470684
0.5349	Remote Similarity	NPC270737
0.5217	Remote Similarity	NPC147224
0.5176	Remote Similarity	NPC197708
0.5111	Remote Similarity	NPC206815

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC474936 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	3003
0.1-0.2	5984
0.2-0.3	159
0.3-0.4	3
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