Natural Product: NPC326316

Natural Product IDNPC326316
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 (+/-)-Nuciferine
IUPAC Name 1,2-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL2414990
PubChem CID 3108374
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0000381] Aporphines

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 ORJVQPIHKOARKV-UHFFFAOYSA-N
Standard InCHI InChI=1S/C19H21NO2/c1-20-9-8-13-11-16(21-2)19(22-3)18-14-7-5-4-6-12(14)10-15(20)17(13)18/h4-7,11,15H,8-10H2,1-3H3
SMILES CN1CCC2=CC(=C(C3=C2C1CC4=CC=CC=C43)OC)OC

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   295.16 Volume:   315.713
?
Van der Waals volume.
Dense:   0.935 LogP:   3.184
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   3.088
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.53
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   2.0 Rigid Bonds:   20.0
TPSA:   21.7
?
Topological Polar Surface Area.
 H-Bond Acceptor:   3.0
H-Bond Donor:   0.0 Rings:   4.0
Heavy Atoms:   3.0

MedChem Properties

QED Drug-Likeness Score:   0.847 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   2.799 Fsp3:   0.368
MCE-18:   69.462
?
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:   0.443 Fluc inhibitor:   0.012
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.622
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.463
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.008 Promiscuous compounds:   0.467

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.415 MDCK Permeability:   -4.719
Pgp-inhibitor:   0.772 Pgp-substrate:   0.136
PAMPA:   0.024
?
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):   0.004
20% Bioavailability (F20%):   0.108 30% Bioavailability (F30%):   0.092
50% Bioavailability (F50%):   0.82

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.97 MRP1:   0.965
Plasma Protein Binding (PPB):   80.346% Volume Distribution (VD):   0.457
Fu: 19.391%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.317
OATP1B3 inhibitor:   0.891 BCRP inhibitor:   0.682
BSEP inhibitor:   0.995

ADMET: Metabolism

CYP1A2-inhibitor:   1.0 CYP1A2-substrate:   0.002
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.007
CYP2C9-inhibitor:   0.804 CYP2C9-substrate:   0.929
CYP2D6-inhibitor:   0.994 CYP2D6-substrate:   0.008
CYP3A4-inhibitor:   0.998 CYP3A4-substrate:   0.389
CYP2B6-substrate:   1.0 CYP2C8-inhibitor:   0.005
HLM stability:   0.834
?
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):  9.92 Half-life (T1/2):  3.988

ADMET: Toxicity

hERG Blockers:  0.556 hERG Blockers (10um):  0.705
Human Hepatotoxicity (H-HT):  0.464 Drug-induced Liver Injury (DILI):  0.008
AMES Toxicity:  0.687 Rat Oral Acute Toxicity:  0.537
Maximum Recommended Daily Dose:  0.754 Skin Sensitization:  0.926
Carcinogencity:  0.778 Eye Corrosion:  0.001
Eye Irritation:  0.101 Respiratory Toxicity:  0.955
Drug-induced Neurotoxicity:  0.69 Ototoxicity:  0.674
Hematotoxicity:  0.141 Drug-induced Nephrotoxicity:  0.079
Genotoxicity:  0.278 RPMI-8226 Immunitoxicity:  0.034
A549 Cytotoxicity:  0.123 Hek293 Cytotoxicity:  0.411
BCF:   2.24
?
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:   4.09
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.373
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.75
?
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
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. n.a. PMID[19919095]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota flower buds and leaves Khon Kaen province, Thailand 2010 PMID[23270663]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota Leaves n.a. n.a. PMID[23642481]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota Flowers n.a. n.a. PMID[26462418]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota Fruit n.a. n.a. Database[FooDB]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota Rhizome n.a. n.a. Database[FooDB]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota Seed n.a. n.a. Database[FooDB]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. Database[FooDB]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO3478 Nelumbo nucifera Species Nelumbonaceae Eukaryota n.a. n.a. n.a. Database[TM-MC]
NPO3478 Nelumbo nucifera Species Nelumbonaceae 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
NPT1858 Individual protein Dopamine D2 receptor Rattus norvegicus Ki = 173.38 nM PMID[23886690]
NPT1857 Individual protein Dopamine D1 receptor Rattus norvegicus Ki = 587.49 nM PMID[23886690]
NPT1858 Individual protein Dopamine D2 receptor Rattus norvegicus Ki = 209.0 nM PMID[23886690]
NPT1857 Individual protein Dopamine D1 receptor Rattus norvegicus Ki = 630.0 nM PMID[23886690]
NPT243 Individual protein Dopamine D2 receptor Homo sapiens IC50 = 14830.0 nM PMID[37172474]
NPT243 Individual protein Dopamine D2 receptor Homo sapiens EC50 = 65.07 nM PMID[37172474]
NPT243 Individual protein Dopamine D2 receptor Homo sapiens Emax = 67.0 % PMID[37172474]
NPT1785 Individual protein Serotonin 7 (5-HT7) receptor Homo sapiens EC50 = 150.0 nM PMID[37172474]
NPT242 Individual protein Dopamine D1 receptor Homo sapiens IC50 = 21760.0 nM PMID[37172474]
NPT290 Individual protein Serotonin 2a (5-HT2a) receptor Homo sapiens IC50 = 478.0 nM PMID[37172474]
NPT292 Individual protein Serotonin 2c (5-HT2c) receptor Homo sapiens IC50 = 131.0 nM PMID[37172474]
NPT243 Individual protein Dopamine D2 receptor Homo sapiens Ki = 173.78 nM PMID[32949964]
NPT4437 Individual protein Aryl hydrocarbon receptor Mus musculus Activity n.a. n.a. n.a. PMID[37154394]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT4590 Cell line EL4 Mus musculus IC50 = 35920.0 nM PMID[37154394]

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 NPC326316 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 NPC81733
0.7895 Intermediate Similarity NPC306902
0.7895 Intermediate Similarity NPC232924
0.7143 Intermediate Similarity NPC99659
0.7143 Intermediate Similarity NPC325871
0.7018 Intermediate Similarity NPC470925
0.6833 Remote Similarity NPC195075
0.6833 Remote Similarity NPC27410
0.6557 Remote Similarity NPC136508
0.625 Remote Similarity NPC266753
0.625 Remote Similarity NPC160298
0.625 Remote Similarity NPC600694
0.619 Remote Similarity NPC205421
0.619 Remote Similarity NPC474931
0.619 Remote Similarity NPC607722
0.6 Remote Similarity NPC219341
0.6 Remote Similarity NPC239854
0.5938 Remote Similarity NPC63997
0.5938 Remote Similarity NPC16805
0.5938 Remote Similarity NPC247389
0.5938 Remote Similarity NPC167546
0.5588 Remote Similarity NPC298979
0.5538 Remote Similarity NPC117188
0.5538 Remote Similarity NPC145832
0.5538 Remote Similarity NPC168753
0.5538 Remote Similarity NPC118274
0.5522 Remote Similarity NPC476432
0.5522 Remote Similarity NPC24264
0.5522 Remote Similarity NPC605845
0.5507 Remote Similarity NPC128560
0.5507 Remote Similarity NPC229166
0.5362 Remote Similarity NPC320223
0.5333 Remote Similarity NPC606311
0.5303 Remote Similarity NPC600388
0.5303 Remote Similarity NPC605949
0.5294 Remote Similarity NPC19520
0.5211 Remote Similarity NPC114364
0.5143 Remote Similarity NPC600118
0.5143 Remote Similarity NPC610764
0.5077 Remote Similarity NPC158376
0.5075 Remote Similarity NPC253043
0.5072 Remote Similarity NPC126284
0.5072 Remote Similarity NPC261206
0.5065 Remote Similarity NPC112248

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC326316 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