Natural Product: NPC38996

Natural Product IDNPC38996
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Endiandrin B
IUPAC Name 4-[(1R,2S,3R,4S)-2-(4-hydroxy-3-methoxyphenyl)-3,4-dimethylcyclobutyl]-2-methoxyphenol
Synonyms Endiandrin B
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL517222
PubChem CID 25242508
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0001392] Lignans, neolignans and related compounds
      • [CHEMONTID:0003419] Cyclobutane lignans

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 QDBUCXMBHJMGCN-JARDSOJUSA-N
Standard InCHI InChI=1S/C20H24O4/c1-11-12(2)20(14-6-8-16(22)18(10-14)24-4)19(11)13-5-7-15(21)17(9-13)23-3/h5-12,19-22H,1-4H3/t11-,12+,19-,20+
SMILES COc1cc(ccc1O)[C@@H]1[C@@H](C)[C@H]([C@@H]1c1ccc(c(c1)OC)O)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   328.17 Volume:   348.149
?
Van der Waals volume.
Dense:   0.943 LogP:   3.094
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.976
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.71
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   16.0
TPSA:   58.92
?
Topological Polar Surface Area.
 H-Bond Acceptor:   4.0
H-Bond Donor:   2.0 Rings:   3.0
Heavy Atoms:   4.0

MedChem Properties

QED Drug-Likeness Score:   0.88 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.511 Fsp3:   0.4
MCE-18:   62.429
?
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:   1 PAINS Alert:   0
Colloidal aggregators:   0.274 Fluc inhibitor:   0.45
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.073
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.005
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.36 Promiscuous compounds:   0.137

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.234 MDCK Permeability:   -4.845
Pgp-inhibitor:   0.492 Pgp-substrate:   0.054
PAMPA:   0.012
?
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):   0.003
20% Bioavailability (F20%):   0.586 30% Bioavailability (F30%):   0.43
50% Bioavailability (F50%):   0.987

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.051 MRP1:   0.967
Plasma Protein Binding (PPB):   91.913% Volume Distribution (VD):   -0.281
Fu: 7.649%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   1.0
OATP1B3 inhibitor:   0.998 BCRP inhibitor:   0.409
BSEP inhibitor:   0.665

ADMET: Metabolism

CYP1A2-inhibitor:   0.996 CYP1A2-substrate:   0.001
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.883
CYP2C9-inhibitor:   0.802 CYP2C9-substrate:   0.818
CYP2D6-inhibitor:   0.188 CYP2D6-substrate:   0.883
CYP3A4-inhibitor:   0.999 CYP3A4-substrate:   1.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   1.0
HLM stability:   0.831
?
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):  5.811 Half-life (T1/2):  1.678

ADMET: Toxicity

hERG Blockers:  0.175 hERG Blockers (10um):  0.561
Human Hepatotoxicity (H-HT):  0.581 Drug-induced Liver Injury (DILI):  0.574
AMES Toxicity:  0.35 Rat Oral Acute Toxicity:  0.302
Maximum Recommended Daily Dose:  0.253 Skin Sensitization:  0.478
Carcinogencity:  0.466 Eye Corrosion:  0.039
Eye Irritation:  0.895 Respiratory Toxicity:  0.799
Drug-induced Neurotoxicity:  0.285 Ototoxicity:  0.548
Hematotoxicity:  0.401 Drug-induced Nephrotoxicity:  0.581
Genotoxicity:  0.231 RPMI-8226 Immunitoxicity:  0.178
A549 Cytotoxicity:  0.687 Hek293 Cytotoxicity:  0.695
BCF:   1.332
?
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:   3.821
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.951
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.398
?
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
NPO18777 Endiandra anthropophagorum Species Lauraceae Eukaryota n.a. Australian n.a. PMID[17583952]
NPO18777 Endiandra anthropophagorum Species Lauraceae Eukaryota n.a. Australian rainforest n.a. PMID[19138858]
NPO18777 Endiandra anthropophagorum Species Lauraceae 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
NPT1144 Individual protein Carbonic anhydrase VB Homo sapiens Kinact = 79.0 nM PMID[19962903]
NPT1143 Individual protein Carbonic anhydrase VA Homo sapiens Kinact = 98.0 nM PMID[19962903]
NPT233 Individual protein Carbonic anhydrase II Homo sapiens Kinact = 12.1 uM PMID[19962903]
NPT3155 Individual protein PROBABLE TRANSMEMBRANE CARBONIC ANHYDRASE (CARBONATE DEHYDRATASE) (CARBONIC DEHYDRATASE) Mycobacterium tuberculosis Ki = 890.0 nM PMID[21215647]
NPT3156 Individual protein Uncharacterized protein Rv1284/MT1322 Mycobacterium tuberculosis Ki = 800.0 nM PubChem BioAssay data set
NPT1148 Individual protein Carbonic anhydrase Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast) Ki = 700.0 nM PMID[20146479]
NPT3157 Individual protein Carbonic anhydrase 2 Cryptococcus neoformans var. grubii Ki = 950.0 nM PMID[17524651]
NPT233 Individual protein Carbonic anhydrase II Homo sapiens Ki = 12100.0 nM PMID[9677265]
NPT947 Individual protein Carbonic anhydrase I Homo sapiens Kinact = 354.0 uM PMID[19962903]
NPT947 Individual protein Carbonic anhydrase I Homo sapiens Ki = 354000.0 nM PMID[21721525]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT81 Cell line A549 Homo sapiens Inhibition = 75.0 % PMID[20923180]
NPT2 Others Unspecified n.a. Ratio Ki = 397.8 n.a. PMID[18180352]
NPT2 Others Unspecified n.a. Ratio Ki = 442.5 n.a. PMID[12027740]
NPT2 Others Unspecified n.a. Ratio Ki = 505.7 n.a. PubChem BioAssay data set
NPT2 Others Unspecified n.a. Ratio Ki = 372.6 n.a. PMID[10075754]
NPT2 Others Unspecified n.a. Ratio Ki = 13.6 n.a. PMID[26970663]
NPT2 Others Unspecified n.a. Ratio Ki = 15.1 n.a. PMID[17461599]
NPT2 Others Unspecified n.a. Ratio Ki = 17.3 n.a. PMID[11975486]
NPT2 Others Unspecified n.a. Ratio Ki = 12.7 n.a. PMID[19331379]

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 NPC38996 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 NPC160380
0.5882 Remote Similarity NPC7097
0.5833 Remote Similarity NPC156840
0.5676 Remote Similarity NPC32163
0.5641 Remote Similarity NPC165133
0.5641 Remote Similarity NPC242885
0.5641 Remote Similarity NPC95614
0.5641 Remote Similarity NPC232316
0.5405 Remote Similarity NPC246358
0.5405 Remote Similarity NPC473264
0.5405 Remote Similarity NPC475815
0.5405 Remote Similarity NPC203719
0.5405 Remote Similarity NPC293619
0.5385 Remote Similarity NPC8547
0.5385 Remote Similarity NPC36108
0.5385 Remote Similarity NPC233731
0.5385 Remote Similarity NPC610203
0.5366 Remote Similarity NPC476343
0.5349 Remote Similarity NPC165045
0.5349 Remote Similarity NPC118533
0.5263 Remote Similarity NPC309203
0.5263 Remote Similarity NPC604189
0.525 Remote Similarity NPC16651
0.525 Remote Similarity NPC181969
0.5238 Remote Similarity NPC282703
0.5238 Remote Similarity NPC184733
0.5238 Remote Similarity NPC128208
0.5238 Remote Similarity NPC129570
0.5238 Remote Similarity NPC63238
0.5238 Remote Similarity NPC602603
0.5227 Remote Similarity NPC239608
0.5227 Remote Similarity NPC46161
0.5128 Remote Similarity NPC257124
0.5116 Remote Similarity NPC480479
0.5116 Remote Similarity NPC195292

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC38996 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
0.5366 Remote Similarity NPD824 Phase 4
0.5128 Remote Similarity NPD228 Phase 0

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