Natural Product: NPC99308

Natural Product IDNPC99308
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 6'-Hydroxy-4'-Methoxyavarone
IUPAC Name 2-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-3-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL465323
PubChem CID 452333
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000012] Lipids and lipid-like molecules
      • [CHEMONTID:0000259] Prenol lipids
        • [CHEMONTID:0001534] Quinone and hydroquinone lipids
          • [CHEMONTID:0002802] Prenylquinones

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 ZEMBAQORKKQPSC-YVUMSICPSA-N
Standard InCHI InChI=1S/C22H30O4/c1-13-7-6-8-18-21(13,3)10-9-14(2)22(18,4)12-15-16(23)11-17(26-5)20(25)19(15)24/h7,11,14,18,24H,6,8-10,12H2,1-5H3/t14-,18+,21+,22+/m0/s1
SMILES COC1=CC(=O)C(=C(C1=O)O)C[C@]1(C)[C@@H](C)CC[C@]2([C@H]1CCC=C2C)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   358.21 Volume:   385.377
?
Van der Waals volume.
Dense:   0.93 LogP:   3.184
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   3.081
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -4.538
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   3.0 Rigid Bonds:   19.0
TPSA:   63.6
?
Topological Polar Surface Area.
 H-Bond Acceptor:   4.0
H-Bond Donor:   1.0 Rings:   3.0
Heavy Atoms:   4.0

MedChem Properties

QED Drug-Likeness Score:   0.588 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.436 Fsp3:   0.636
MCE-18:   56.222
?
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:   1
Colloidal aggregators:   0.538 Fluc inhibitor:   0.744
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.131
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.086
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.651 Promiscuous compounds:   0.339

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.597 MDCK Permeability:   -4.622
Pgp-inhibitor:   0.764 Pgp-substrate:   0.007
PAMPA:   0.306
?
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):   0.025
20% Bioavailability (F20%):   0.175 30% Bioavailability (F30%):   0.651
50% Bioavailability (F50%):   0.98

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.116 MRP1:   0.674
Plasma Protein Binding (PPB):   95.933% Volume Distribution (VD):   0.071
Fu: 3.722%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   1.0
OATP1B3 inhibitor:   1.0 BCRP inhibitor:   0.221
BSEP inhibitor:   0.99

ADMET: Metabolism

CYP1A2-inhibitor:   0.368 CYP1A2-substrate:   0.808
CYP2C19-inhibitor:   0.082 CYP2C19-substrate:   0.392
CYP2C9-inhibitor:   0.108 CYP2C9-substrate:   0.001
CYP2D6-inhibitor:   0.001 CYP2D6-substrate:   0.186
CYP3A4-inhibitor:   0.0 CYP3A4-substrate:   0.745
CYP2B6-substrate:   0.001 CYP2C8-inhibitor:   0.75
HLM stability:   0.996
?
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):  7.829 Half-life (T1/2):  0.789

ADMET: Toxicity

hERG Blockers:  0.018 hERG Blockers (10um):  0.138
Human Hepatotoxicity (H-HT):  0.674 Drug-induced Liver Injury (DILI):  0.538
AMES Toxicity:  0.4 Rat Oral Acute Toxicity:  0.312
Maximum Recommended Daily Dose:  0.47 Skin Sensitization:  0.944
Carcinogencity:  0.929 Eye Corrosion:  0.119
Eye Irritation:  0.913 Respiratory Toxicity:  0.605
Drug-induced Neurotoxicity:  0.264 Ototoxicity:  0.202
Hematotoxicity:  0.577 Drug-induced Nephrotoxicity:  0.542
Genotoxicity:  0.581 RPMI-8226 Immunitoxicity:  0.084
A549 Cytotoxicity:  0.136 Hek293 Cytotoxicity:  0.308
BCF:   2.175
?
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:   4.9
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   6.354
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   5.937
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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
NPO33143 Dysidea cinerea Species n.a. n.a. n.a. n.a. n.a. PMID[1710654]
NPO33143 Dysidea cinerea Species n.a. n.a. n.a. n.a. n.a. PMID[31532203]
NPO33143 Dysidea cinerea Species 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

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
NPT168 Cell line P388 Mus musculus IC50 > 20.0 ug.mL-1 PMID[16180804]
NPT168 Cell line P388 Mus musculus IC50 > 54.0 nM PMID[33940466]

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 NPC99308 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
0.7368 Intermediate Similarity NPC263997
0.7368 Intermediate Similarity NPC8518
0.6557 Remote Similarity NPC489707
0.6316 Remote Similarity NPC55869
0.6 Remote Similarity NPC608337
0.5902 Remote Similarity NPC489061
0.5538 Remote Similarity NPC604451
0.5469 Remote Similarity NPC241512
0.5469 Remote Similarity NPC6185
0.5469 Remote Similarity NPC603829
0.5429 Remote Similarity NPC72688
0.541 Remote Similarity NPC108955
0.5373 Remote Similarity NPC34193
0.5373 Remote Similarity NPC218631
0.5373 Remote Similarity NPC606042
0.5323 Remote Similarity NPC475833
0.5294 Remote Similarity NPC489062
0.5283 Remote Similarity NPC606666
0.5167 Remote Similarity NPC260474

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC99308 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