Natural Product: NPC18576

Natural Product IDNPC18576
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Isocubebin
IUPAC Name (R)-1,3-benzodioxol-5-yl-[(3R,4R)-4-(1,3-benzodioxol-5-ylmethyl)oxolan-3-yl]methanol
Synonyms Isocubebin
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL578223
PubChem CID 45481962
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0001392] Lignans, neolignans and related compounds
      • [CHEMONTID:0003686] Furanoid lignans
        • [CHEMONTID:0001604] Tetrahydrofuran lignans
          • [CHEMONTID:0003424] 9,9'-epoxylignans

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 DQAKTWJMKAIIDV-AVYPCKFXSA-N
Standard InCHI InChI=1S/C20H20O6/c21-20(13-2-4-17-19(7-13)26-11-24-17)15-9-22-8-14(15)5-12-1-3-16-18(6-12)25-10-23-16/h1-4,6-7,14-15,20-21H,5,8-11H2/t14-,15-,20-/m0/s1
SMILES O[C@H]([C@H]1COC[C@@H]1Cc1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   356.13 Volume:   348.616
?
Van der Waals volume.
Dense:   1.022 LogP:   1.794
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.85
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.447
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   25.0
TPSA:   66.38
?
Topological Polar Surface Area.
 H-Bond Acceptor:   6.0
H-Bond Donor:   1.0 Rings:   5.0
Heavy Atoms:   6.0

MedChem Properties

QED Drug-Likeness Score:   0.909 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.598 Fsp3:   0.4
MCE-18:   82.286
?
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:   0.565 Fluc inhibitor:   0.669
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.056
?
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:   0.093 Promiscuous compounds:   0.084

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.828 MDCK Permeability:   -4.762
Pgp-inhibitor:   0.335 Pgp-substrate:   0.019
PAMPA:   0.329
?
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%):   0.049 30% Bioavailability (F30%):   0.0
50% Bioavailability (F50%):   0.271

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.835 MRP1:   0.407
Plasma Protein Binding (PPB):   94.968% Volume Distribution (VD):   0.68
Fu: 6.221%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.456
OATP1B3 inhibitor:   0.284 BCRP inhibitor:   0.003
BSEP inhibitor:   1.0

ADMET: Metabolism

CYP1A2-inhibitor:   0.034 CYP1A2-substrate:   0.775
CYP2C19-inhibitor:   0.986 CYP2C19-substrate:   0.193
CYP2C9-inhibitor:   0.639 CYP2C9-substrate:   1.0
CYP2D6-inhibitor:   1.0 CYP2D6-substrate:   1.0
CYP3A4-inhibitor:   0.954 CYP3A4-substrate:   0.999
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.0
HLM stability:   0.171
?
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):  3.645 Half-life (T1/2):  1.29

ADMET: Toxicity

hERG Blockers:  0.275 hERG Blockers (10um):  0.476
Human Hepatotoxicity (H-HT):  0.842 Drug-induced Liver Injury (DILI):  0.94
AMES Toxicity:  0.678 Rat Oral Acute Toxicity:  0.259
Maximum Recommended Daily Dose:  0.586 Skin Sensitization:  0.741
Carcinogencity:  0.894 Eye Corrosion:  0.016
Eye Irritation:  0.786 Respiratory Toxicity:  0.523
Drug-induced Neurotoxicity:  0.931 Ototoxicity:  0.805
Hematotoxicity:  0.316 Drug-induced Nephrotoxicity:  0.92
Genotoxicity:  0.812 RPMI-8226 Immunitoxicity:  0.149
A549 Cytotoxicity:  0.133 Hek293 Cytotoxicity:  0.351
BCF:   1.118
?
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:   3.556
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.363
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.431
?
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
NPO12339 Daphne feddei Species Thymelaeaceae Eukaryota stem bark Kunming, Yunnan Province, China n.a. PMID[18986199]
NPO23754 Solanum aculeatissimum Species Solanaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO12339 Daphne feddei Species Thymelaeaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO21329 Ilyonectria destructans Species Nectriaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO10211 Pajanelia multijuga n.a. n.a. n.a. n.a. n.a. n.a. Database[COCONUT]
NPO23754 Solanum aculeatissimum Species Solanaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO21329 Ilyonectria destructans Species Nectriaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO23754 Solanum aculeatissimum Species Solanaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO10211 Pajanelia multijuga n.a. n.a. n.a. n.a. n.a. n.a. Database[UNPD]
NPO12339 Daphne feddei Species Thymelaeaceae 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

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
NPT113 Cell line RAW264.7 Mus musculus IC50 > 300000.0 nM PMID[18986199]

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 NPC18576 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
0.7083 Intermediate Similarity NPC600801
0.6842 Remote Similarity NPC3982
0.6296 Remote Similarity NPC192255
0.6296 Remote Similarity NPC104077
0.6296 Remote Similarity NPC219671
0.6296 Remote Similarity NPC147616
0.6154 Remote Similarity NPC476748
0.5893 Remote Similarity NPC171550
0.5893 Remote Similarity NPC134764
0.5873 Remote Similarity NPC56184
0.5517 Remote Similarity NPC143895
0.55 Remote Similarity NPC475875
0.549 Remote Similarity NPC259742
0.5439 Remote Similarity NPC110958
0.5439 Remote Similarity NPC19890
0.5385 Remote Similarity NPC40352
0.5385 Remote Similarity NPC213711
0.5323 Remote Similarity NPC47181
0.5323 Remote Similarity NPC185908
0.5323 Remote Similarity NPC218471
0.5323 Remote Similarity NPC239818
0.5323 Remote Similarity NPC482891
0.5254 Remote Similarity NPC158737
0.5152 Remote Similarity NPC487679
0.5152 Remote Similarity NPC487678
0.5098 Remote Similarity NPC80241
0.5098 Remote Similarity NPC301641
0.5098 Remote Similarity NPC485483
0.5082 Remote Similarity NPC205915
0.5077 Remote Similarity NPC106739
0.5077 Remote Similarity NPC161249
0.5075 Remote Similarity NPC169973

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC18576 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