Natural Product: NPC98557

Natural Product IDNPC98557
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Eupatolide
IUPAC Name (3aR,4R,6E,10E,11aR)-4-hydroxy-6,10-dimethyl-3-methylidene-3a,4,5,8,9,11a-hexahydrocyclodeca[b]furan-2-one
Synonyms Eupatolide
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL485296
PubChem CID 5281460
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000012] Lipids and lipid-like molecules
      • [CHEMONTID:0000259] Prenol lipids
        • [CHEMONTID:0001283] Terpene lactones
          • [CHEMONTID:0001543] Sesquiterpene lactones
            • [CHEMONTID:0001771] Germacranolides and derivatives

The Chemical Classification was calculated by Classyfire, a software for chemical taxonomy calculation. Reference: DOI:10.1186/s13321-016-0174-y.

  Chemical Representations

Standard InCHIKey PDEJECFRCJOMEN-OURLZOILSA-N
Standard InCHI InChI=1S/C15H20O3/c1-9-5-4-6-10(2)8-13-14(12(16)7-9)11(3)15(17)18-13/h5,8,12-14,16H,3-4,6-7H2,1-2H3/b9-5+,10-8+/t12-,13-,14-/m1/s1
SMILES C/C/1=C[C@H]2OC(=O)C(=C)[C@@H]2[C@@H](C/C(=C/CC1)/C)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   248.14 Volume:   266.708
?
Van der Waals volume.
Dense:   0.93 LogP:   1.921
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.869
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.825
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   0.0 Rigid Bonds:   16.0
TPSA:   46.53
?
Topological Polar Surface Area.
 H-Bond Acceptor:   3.0
H-Bond Donor:   1.0 Rings:   2.0
Heavy Atoms:   3.0

MedChem Properties

QED Drug-Likeness Score:   0.407 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.539 Fsp3:   0.533
MCE-18:   32.783
?
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:   1
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.314 Fluc inhibitor:   0.012
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.328
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.047
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.708 Promiscuous compounds:   0.302

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.055 MDCK Permeability:   -4.826
Pgp-inhibitor:   0.869 Pgp-substrate:   0.19
PAMPA:   0.224
?
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):   0.155
20% Bioavailability (F20%):   0.41 30% Bioavailability (F30%):   0.75
50% Bioavailability (F50%):   0.877

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.002 MRP1:   0.632
Plasma Protein Binding (PPB):   75.663% Volume Distribution (VD):   -0.154
Fu: 18.837%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.999
OATP1B3 inhibitor:   0.976 BCRP inhibitor:   0.026
BSEP inhibitor:   0.951

ADMET: Metabolism

CYP1A2-inhibitor:   0.007 CYP1A2-substrate:   0.014
CYP2C19-inhibitor:   0.461 CYP2C19-substrate:   0.002
CYP2C9-inhibitor:   0.093 CYP2C9-substrate:   0.005
CYP2D6-inhibitor:   0.522 CYP2D6-substrate:   0.117
CYP3A4-inhibitor:   0.174 CYP3A4-substrate:   0.871
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.675
HLM stability:   0.432
?
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):  8.209 Half-life (T1/2):  1.823

ADMET: Toxicity

hERG Blockers:  0.019 hERG Blockers (10um):  0.105
Human Hepatotoxicity (H-HT):  0.773 Drug-induced Liver Injury (DILI):  0.954
AMES Toxicity:  0.587 Rat Oral Acute Toxicity:  0.173
Maximum Recommended Daily Dose:  0.433 Skin Sensitization:  0.99
Carcinogencity:  0.612 Eye Corrosion:  0.067
Eye Irritation:  0.937 Respiratory Toxicity:  0.08
Drug-induced Neurotoxicity:  0.614 Ototoxicity:  0.392
Hematotoxicity:  0.716 Drug-induced Nephrotoxicity:  0.913
Genotoxicity:  0.586 RPMI-8226 Immunitoxicity:  0.161
A549 Cytotoxicity:  0.11 Hek293 Cytotoxicity:  0.228
BCF:   1.3
?
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:   3.917
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.468
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.839
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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
NPO33469 Asteraceae Family Asteraceae Eukaryota n.a. n.a. n.a. PMID[18329753]
NPO33469 Asteraceae Family Asteraceae Eukaryota 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

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
NPT91 Cell line KB Homo sapiens ED50 = 5.0 umol/L PMID[11325240]
NPT113 Cell line RAW264.7 Mus musculus IC50 = 7300.0 nM PMID[33939429]
NPT113 Cell line RAW264.7 Mus musculus Activity n.a. n.a. n.a. PMID[33939429]
NPT28438 Unchecked Unchecked n.a. IC50 = 12200.0 nM PMID[33939429]

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
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 NPC98557 and all remaining natural products in the NPASS database.
●  The right table: Most similar natural products (Tc>=0.5 or Top200).

Similarity Score Similarity Level Natural Product ID
1.0 High Similarity NPC167881
0.7907 Intermediate Similarity NPC229825
0.7907 Intermediate Similarity NPC24417
0.7907 Intermediate Similarity NPC59097
0.7907 Intermediate Similarity NPC602858
0.7111 Intermediate Similarity NPC473715
0.64 Remote Similarity NPC473619
0.6 Remote Similarity NPC58956
0.6 Remote Similarity NPC163003
0.6 Remote Similarity NPC295633
0.6 Remote Similarity NPC269206
0.5686 Remote Similarity NPC7563
0.5625 Remote Similarity NPC171204
0.5625 Remote Similarity NPC606745
0.5577 Remote Similarity NPC475302
0.551 Remote Similarity NPC611318
0.5472 Remote Similarity NPC488117
0.5472 Remote Similarity NPC178702
0.54 Remote Similarity NPC68819
0.537 Remote Similarity NPC320630
0.537 Remote Similarity NPC250315
0.5273 Remote Similarity NPC470755
0.5273 Remote Similarity NPC488116
0.5273 Remote Similarity NPC298801
0.52 Remote Similarity NPC196653
0.5192 Remote Similarity NPC470256
0.5192 Remote Similarity NPC476355
0.5185 Remote Similarity NPC481909

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC98557 and all drugs/candidates.
●  The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

Similarity Score Similarity Level Drug ID Developmental Stage
NPD

Bioactivity similarity

  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