Natural Product: NPC46536

Natural Product IDNPC46536
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Polyaltic Acid
IUPAC Name (1R,4aR,5S,8aR)-5-[2-(furan-3-yl)ethyl]-1,4a-dimethyl-6-methylidene-3,4,5,7,8,8a-hexahydro-2H-naphthalene-1-carboxylic acid
Synonyms Polyaltic Acid
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL2048916
PubChem CID 10245240
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000012] Lipids and lipid-like molecules
      • [CHEMONTID:0000259] Prenol lipids
        • [CHEMONTID:0001551] Diterpenoids
          • [CHEMONTID:0001757] Colensane and clerodane diterpenoids

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 ZQHJXKYYELWEOK-ONCXSQPRSA-N
Standard InCHI InChI=1S/C20H28O3/c1-14-5-8-17-19(2,10-4-11-20(17,3)18(21)22)16(14)7-6-15-9-12-23-13-15/h9,12-13,16-17H,1,4-8,10-11H2,2-3H3,(H,21,22)/t16-,17+,19+,20+/m0/s1
SMILES C=C1CC[C@@H]2[C@]([C@H]1CCc1cocc1)(C)CCC[C@@]2(C)C(=O)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   316.2 Volume:   344.632
?
Van der Waals volume.
Dense:   0.918 LogP:   3.799
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   3.086
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.994
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   18.0
TPSA:   50.44
?
Topological Polar Surface Area.
 H-Bond Acceptor:   3.0
H-Bond Donor:   1.0 Rings:   3.0
Heavy Atoms:   3.0

MedChem Properties

QED Drug-Likeness Score:   0.788 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.051 Fsp3:   0.65
MCE-18:   70.909
?
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:   0.323 Fluc inhibitor:   0.001
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.005
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.009
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.446 Promiscuous compounds:   0.028

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.215 MDCK Permeability:   -4.778
Pgp-inhibitor:   0.723 Pgp-substrate:   0.001
PAMPA:   0.25
?
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):   0.026
20% Bioavailability (F20%):   0.167 30% Bioavailability (F30%):   0.212
50% Bioavailability (F50%):   0.299

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.003 MRP1:   0.87
Plasma Protein Binding (PPB):   98.018% Volume Distribution (VD):   -0.191
Fu: 2.164%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.996
OATP1B3 inhibitor:   0.901 BCRP inhibitor:   0.109
BSEP inhibitor:   0.992

ADMET: Metabolism

CYP1A2-inhibitor:   0.221 CYP1A2-substrate:   0.002
CYP2C19-inhibitor:   0.42 CYP2C19-substrate:   0.005
CYP2C9-inhibitor:   0.339 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.0 CYP2D6-substrate:   0.002
CYP3A4-inhibitor:   0.964 CYP3A4-substrate:   0.069
CYP2B6-substrate:   0.178 CYP2C8-inhibitor:   0.852
HLM stability:   0.156
?
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):  2.822 Half-life (T1/2):  1.037

ADMET: Toxicity

hERG Blockers:  0.073 hERG Blockers (10um):  0.093
Human Hepatotoxicity (H-HT):  0.551 Drug-induced Liver Injury (DILI):  0.805
AMES Toxicity:  0.166 Rat Oral Acute Toxicity:  0.465
Maximum Recommended Daily Dose:  0.744 Skin Sensitization:  0.888
Carcinogencity:  0.679 Eye Corrosion:  0.232
Eye Irritation:  0.941 Respiratory Toxicity:  0.773
Drug-induced Neurotoxicity:  0.034 Ototoxicity:  0.46
Hematotoxicity:  0.291 Drug-induced Nephrotoxicity:  0.773
Genotoxicity:  0.621 RPMI-8226 Immunitoxicity:  0.036
A549 Cytotoxicity:  0.036 Hek293 Cytotoxicity:  0.083
BCF:   1.496
?
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:   4.19
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.594
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.985
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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
NPO32774 Copaifera Genus Fabaceae Eukaryota n.a. n.a. n.a. PMID[22440015]

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
NPT2679 Cell line LLC-MK2 Macaca mulatta CC50 = 60100.0 nM PMID[26186150]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi IC50 = 167700.0 nM PMID[25310730]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi EC50 = 965100.0 nM PMID[23805957]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi IC50 = 28400.0 nM PMID[23434030]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 38.0 % PMID[8350092]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 26.71 % PubChem BioAssay data set
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 25.8 % PubChem BioAssay data set
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 29.09 % PubChem BioAssay data set
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 16.7 % PMID[26684850]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 1.85 % PMID[26684850]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 0.91 % PMID[26684850]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 95.96 % PMID[26562541]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi Activity = 1.28 % PMID[25946116]

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 NPC46536 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 NPC138139
1.0 High Similarity NPC603180
0.623 Remote Similarity NPC485404
0.5507 Remote Similarity NPC16922
0.5484 Remote Similarity NPC488498
0.5484 Remote Similarity NPC61952
0.5484 Remote Similarity NPC481630
0.5484 Remote Similarity NPC603184
0.5469 Remote Similarity NPC18819
0.5469 Remote Similarity NPC46610
0.5397 Remote Similarity NPC198240
0.5397 Remote Similarity NPC237591
0.5397 Remote Similarity NPC72343
0.5397 Remote Similarity NPC36616
0.5397 Remote Similarity NPC3753
0.5312 Remote Similarity NPC59436
0.5231 Remote Similarity NPC471159
0.5231 Remote Similarity NPC123880
0.5231 Remote Similarity NPC91369
0.5217 Remote Similarity NPC130275
0.5152 Remote Similarity NPC269543
0.5152 Remote Similarity NPC247783
0.5152 Remote Similarity NPC239098
0.5079 Remote Similarity NPC485403

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC46536 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