NPASS Compound

Natural Product: NPC18819

Natural Product ID	NPC18819
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Cupressicacid
IUPAC Name	(1S,4aR,5S,8aR)-5-[(3R)-3-hydroxy-3-methylpent-4-enyl]-1,4a-dimethyl-6-methylidene-3,4,5,7,8,8a-hexahydro-2H-naphthalene-1-carboxylic acid
Synonyms	Cupressicacid
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL457163
PubChem CID	44584269
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000012] Lipids and lipid-like molecules [CHEMONTID:0000259] Prenol lipids [CHEMONTID:0001551] Diterpenoids

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 55 56 0 0 0 0 0 0 0 0999 V2000 4.9384 1.9264 1.2420 C 0 0 0 0 0 0 0 0 0 0 0 0 5.1757 0.9171 0.4396 C 0 0 0 0 0 0 0 0 0 0 0 0 4.0909 0.1121 -0.1351 C 0 0 1 0 0 0 0 0 0 0 0 0 4.1906 -1.2878 0.4331 C 0 0 0 0 0 0 0 0 0 0 0 0 2.7247 0.7154 0.2104 C 0 0 0 0 0 0 0 0 0 0 0 0 1.6613 -0.1665 -0.4145 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3548 0.3782 -0.1179 C 0 0 1 0 0 0 0 0 0 0 0 0 0.0411 1.7446 -0.6280 C 0 0 0 0 0 0 0 0 0 0 0 0 0.7193 2.3741 -1.5597 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.1745 2.4122 -0.0528 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.3774 1.4909 -0.1609 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.9881 0.1470 0.3613 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.8899 -0.4223 -0.4831 C 0 0 1 0 0 0 0 0 0 0 0 0 -1.0540 -0.1226 -1.9832 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7180 -1.8935 -0.3807 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.3045 -2.3423 0.9480 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.8171 -2.1943 0.7681 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.1598 -0.7264 0.6643 C 0 0 1 0 0 0 0 0 0 0 0 0 -3.6801 -0.3577 2.0521 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2869 -0.6053 -0.2532 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.4067 -0.2405 0.1840 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.2581 -0.8592 -1.6120 O 0 0 0 0 0 0 0 0 0 0 0 0 4.1935 0.0248 -1.5121 O 0 0 0 0 0 0 0 0 0 0 0 0 3.9266 2.1821 1.4939 H 0 0 0 0 0 0 0 0 0 0 0 0 5.7453 2.5008 1.6504 H 0 0 0 0 0 0 0 0 0 0 0 0 6.1986 0.6701 0.1938 H 0 0 0 0 0 0 0 0 0 0 0 0 3.5474 -1.3415 1.3107 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9371 -2.0207 -0.3508 H 0 0 0 0 0 0 0 0 0 0 0 0 5.2472 -1.4904 0.7179 H 0 0 0 0 0 0 0 0 0 0 0 0 2.6339 0.6135 1.3366 H 0 0 0 0 0 0 0 0 0 0 0 0 2.7345 1.7471 -0.1025 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9378 -0.2541 -1.4850 H 0 0 0 0 0 0 0 0 0 0 0 0 1.7862 -1.1413 0.1034 H 0 0 0 0 0 0 0 0 0 0 0 0 0.2799 0.4783 1.0102 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4102 3.3736 -1.8629 H 0 0 0 0 0 0 0 0 0 0 0 0 1.5898 1.9710 -2.0930 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9985 2.6683 1.0077 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.4290 3.3421 -0.5838 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.8777 1.5098 -1.1230 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1288 1.9218 0.5685 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5094 0.3597 1.3715 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2570 0.9232 -2.1901 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6712 -0.8620 -2.4935 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0143 -0.3029 -2.4012 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.3848 -2.3679 -1.1637 H 0 0 0 0 0 0 0 0 0 0 0 0 0.2675 -2.2932 -0.5704 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.0076 -1.5950 1.6944 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.0292 -3.3747 1.1829 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.0804 -2.7533 -0.1626 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3069 -2.7060 1.6014 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1489 -0.9710 2.8355 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.4175 0.6952 2.2944 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7465 -0.5555 2.1697 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.1067 -1.0950 -2.1163 H 0 0 0 0 0 0 0 0 0 0 0 0 3.8978 -0.8562 -1.8538 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 2 3 1 0 3 4 1 0 3 5 1 0 5 6 1 0 6 7 1 0 7 8 1 0 8 9 2 0 8 10 1 0 10 11 1 0 11 12 1 0 12 13 1 0 13 14 1 6 13 15 1 0 15 16 1 0 16 17 1 0 17 18 1 0 18 19 1 1 18 20 1 0 20 21 2 0 20 22 1 0 3 23 1 6 13 7 1 0 18 12 1 0 1 24 1 0 1 25 1 0 2 26 1 0 4 27 1 0 4 28 1 0 4 29 1 0 5 30 1 0 5 31 1 0 6 32 1 0 6 33 1 0 7 34 1 1 9 35 1 0 9 36 1 0 10 37 1 0 10 38 1 0 11 39 1 0 11 40 1 0 12 41 1 1 14 42 1 0 14 43 1 0 14 44 1 0 15 45 1 0 15 46 1 0 16 47 1 0 16 48 1 0 17 49 1 0 17 50 1 0 19 51 1 0 19 52 1 0 19 53 1 0 22 54 1 0 23 55 1 0 M END

Standard InCHIKey	LMODNMXJBXUOQF-ZRSLWSEBSA-N
Standard InCHI	InChI=1S/C20H32O3/c1-6-18(3,23)13-10-15-14(2)8-9-16-19(15,4)11-7-12-20(16,5)17(21)22/h6,15-16,23H,1-2,7-13H2,3-5H3,(H,21,22)/t15-,16+,18-,19+,20-/m0/s1
SMILES	C=C[C@@](C)(CC[C@H]1C(=C)CC[C@@H]2[C@]1(C)CCC[C@]2(C)C(=O)O)O

Calculated Properties

Physi-Chem Properties

Molecular Weight:	320.24	Volume:	355.825 ? Van der Waals volume.
Dense:	0.9	LogP:	3.071 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.646 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-4.0 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	5.0	Rigid Bonds:	14.0
TPSA:	57.53 ? Topological Polar Surface Area.	H-Bond Acceptor:	3.0
H-Bond Donor:	2.0	Rings:	2.0
Heavy Atoms:	3.0

MedChem Properties

QED Drug-Likeness Score:	0.73	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	4.395	Fsp³:	0.75
MCE-18:	47.771 ? 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:	0.096	Fluc inhibitor:	0.0 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.003 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.001 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.908	Promiscuous compounds:	0.111

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.698	MDCK Permeability:	-4.796
Pgp-inhibitor:	0.028	Pgp-substrate:	0.0
PAMPA:	0.638 ? 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%):	0.241	30% Bioavailability (F30%):	0.139
50% Bioavailability (F50%):	0.842

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.002	MRP1:	0.768
Plasma Protein Binding (PPB):	89.403%	Volume Distribution (VD):	-0.376
Fu:	5.843% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	1.0
OATP1B3 inhibitor:	1.0	BCRP inhibitor:	0.032
BSEP inhibitor:	0.921

ADMET: Metabolism

CYP1A2-inhibitor:	0.111	CYP1A2-substrate:	0.001
CYP2C19-inhibitor:	0.08	CYP2C19-substrate:	0.0
CYP2C9-inhibitor:	0.978	CYP2C9-substrate:	0.0
CYP2D6-inhibitor:	0.0	CYP2D6-substrate:	0.0
CYP3A4-inhibitor:	0.978	CYP3A4-substrate:	0.208
CYP2B6-substrate:	0.033	CYP2C8-inhibitor:	0.153
HLM stability:	0.111 ? 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):

2.787

Half-life (T1/2):

1.186

ADMET: Toxicity

hERG Blockers:	0.022	hERG Blockers (10um):	0.103
Human Hepatotoxicity (H-HT):	0.695	Drug-induced Liver Injury (DILI):	0.176
AMES Toxicity:	0.14	Rat Oral Acute Toxicity:	0.397
Maximum Recommended Daily Dose:	0.56	Skin Sensitization:	0.973
Carcinogencity:	0.848	Eye Corrosion:	0.93
Eye Irritation:	0.989	Respiratory Toxicity:	0.949
Drug-induced Neurotoxicity:	0.373	Ototoxicity:	0.355
Hematotoxicity:	0.145	Drug-induced Nephrotoxicity:	0.685
Genotoxicity:	0.513	RPMI-8226 Immunitoxicity:	0.032
A549 Cytotoxicity:	0.053	Hek293 Cytotoxicity:	0.152
BCF:	0.779 ? 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:	3.725 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.373 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.668 ? 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
NPO30782	Brazilian propolis	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	DOI[10.1248/cpb.47.1521]
NPO30782	Brazilian propolis	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	PMID[11000036]
NPO30782	Brazilian propolis	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	PMID[8951168]
NPO30782	Brazilian propolis	n.a.	n.a.	n.a.	n.a.	Brazilian propolis	n.a.	PMID[9677271]
NPO30782	Brazilian propolis	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[COCONUT]

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
ED50	2

Activity Type	# Activity
Cell line	1
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
NPT453	Cell line	HT-1080	Homo sapiens	ED50	=	94.86	ug ml-1	PMID[18280170]
NPT20529	Non-molecular	NON-PROTEIN TARGET	n.a.	ED50	>	100.0	ug ml-1	PMID[9677271]

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 NPC18819 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	19653
0.1-0.2	26235
0.2-0.3	3602
0.3-0.4	222
0.4-0.5	97
0.5-0.6	23
0.6-0.7	21
0.7-0.8	0
0.8-0.85	0
0.85-0.9	0
0.9-0.95	0
0.95-1	1

Similarity Score	Similarity Level	Natural Product ID
1.0	High Similarity	NPC46610
0.717	Intermediate Similarity	NPC239098
0.7059	Intermediate Similarity	NPC481630
0.6981	Remote Similarity	NPC91369
0.6852	Remote Similarity	NPC269543
0.6852	Remote Similarity	NPC247783
0.6731	Remote Similarity	NPC488498
0.6731	Remote Similarity	NPC61952
0.6731	Remote Similarity	NPC603184
0.6604	Remote Similarity	NPC198240
0.6604	Remote Similarity	NPC237591
0.6604	Remote Similarity	NPC72343
0.6604	Remote Similarity	NPC36616
0.6604	Remote Similarity	NPC3753
0.6552	Remote Similarity	NPC477782
0.6491	Remote Similarity	NPC232344
0.6481	Remote Similarity	NPC59436
0.6441	Remote Similarity	NPC477783
0.6364	Remote Similarity	NPC471159
0.6364	Remote Similarity	NPC123880
0.6316	Remote Similarity	NPC40228
0.6207	Remote Similarity	NPC600691
0.6	Remote Similarity	NPC14203
0.6	Remote Similarity	NPC229584
0.5818	Remote Similarity	NPC99154
0.5763	Remote Similarity	NPC144278
0.5714	Remote Similarity	NPC161923
0.5714	Remote Similarity	NPC183503
0.5714	Remote Similarity	NPC283908
0.5714	Remote Similarity	NPC103958
0.5714	Remote Similarity	NPC610917
0.5484	Remote Similarity	NPC479671
0.5469	Remote Similarity	NPC46536
0.5469	Remote Similarity	NPC138139
0.5469	Remote Similarity	NPC603180
0.5345	Remote Similarity	NPC104806
0.5345	Remote Similarity	NPC165711
0.5345	Remote Similarity	NPC109854
0.5283	Remote Similarity	NPC41160
0.5283	Remote Similarity	NPC67840
0.5185	Remote Similarity	NPC476406
0.5172	Remote Similarity	NPC170985
0.5167	Remote Similarity	NPC82979
0.5167	Remote Similarity	NPC607026
0.5167	Remote Similarity	NPC610334
0.5161	Remote Similarity	NPC48107
0.5082	Remote Similarity	NPC483605

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC18819 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	5891
0.1-0.2	3082
0.2-0.3	175
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