Natural Product: NPC476571

Natural Product IDNPC476571
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Reticuline
IUPAC Name (1S)-1-[(3-hydroxy-4-methoxyphenyl)methyl]-6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-7-ol
Synonyms (+)-Reticuline Trifluoroacetate
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL235212
PubChem CID 439653
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000002] Organoheterocyclic compounds
      • [CHEMONTID:0002566] Isoquinolines and derivatives
        • [CHEMONTID:0000054] Benzylisoquinolines

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 BHLYRWXGMIUIHG-HNNXBMFYSA-N
Standard InCHI InChI=1S/C19H23NO4/c1-20-7-6-13-10-19(24-3)17(22)11-14(13)15(20)8-12-4-5-18(23-2)16(21)9-12/h4-5,9-11,15,21-22H,6-8H2,1-3H3/t15-/m0/s1
SMILES CN1CCC2=CC(=C(C=C2[C@@H]1CC3=CC(=C(C=C3)OC)O)O)OC

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   329.16 Volume:   341.85
?
Van der Waals volume.
Dense:   0.963 LogP:   1.839
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.975
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.913
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   17.0
TPSA:   62.16
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   2.0 Rings:   3.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.903 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   2.806 Fsp3:   0.368
MCE-18:   58.154
?
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:   1 PAINS Alert:   0
Colloidal aggregators:   0.397 Fluc inhibitor:   0.026
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.509
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.465
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.005 Promiscuous compounds:   0.217

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.036 MDCK Permeability:   -4.752
Pgp-inhibitor:   0.5 Pgp-substrate:   0.158
PAMPA:   0.031
?
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):   0.012
20% Bioavailability (F20%):   0.826 30% Bioavailability (F30%):   0.679
50% Bioavailability (F50%):   0.987

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.526 MRP1:   0.917
Plasma Protein Binding (PPB):   47.672% Volume Distribution (VD):   -0.174
Fu: 50.52%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.991
OATP1B3 inhibitor:   0.985 BCRP inhibitor:   0.829
BSEP inhibitor:   0.775

ADMET: Metabolism

CYP1A2-inhibitor:   1.0 CYP1A2-substrate:   0.001
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.0
CYP2C9-inhibitor:   1.0 CYP2C9-substrate:   0.993
CYP2D6-inhibitor:   1.0 CYP2D6-substrate:   0.004
CYP3A4-inhibitor:   0.998 CYP3A4-substrate:   0.005
CYP2B6-substrate:   0.996 CYP2C8-inhibitor:   0.312
HLM stability:   0.551
?
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):  5.274 Half-life (T1/2):  2.451

ADMET: Toxicity

hERG Blockers:  0.352 hERG Blockers (10um):  0.6
Human Hepatotoxicity (H-HT):  0.747 Drug-induced Liver Injury (DILI):  0.15
AMES Toxicity:  0.609 Rat Oral Acute Toxicity:  0.266
Maximum Recommended Daily Dose:  0.848 Skin Sensitization:  0.781
Carcinogencity:  0.429 Eye Corrosion:  0.003
Eye Irritation:  0.826 Respiratory Toxicity:  0.667
Drug-induced Neurotoxicity:  0.706 Ototoxicity:  0.58
Hematotoxicity:  0.117 Drug-induced Nephrotoxicity:  0.229
Genotoxicity:  0.59 RPMI-8226 Immunitoxicity:  0.079
A549 Cytotoxicity:  0.179 Hek293 Cytotoxicity:  0.577
BCF:   1.207
?
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:   3.637
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.925
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.194
?
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
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. stem wood n.a. DOI[10.1021/np100247r]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. PMID[10395501]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. PMID[10425140]
NPO6333 Annona glabra Species Annonaceae Eukaryota Fruits n.a. n.a. PMID[15568797]
NPO6333 Annona glabra Species Annonaceae Eukaryota stem Taipei Botanical Garden, Taipei, Taiwan, China 2006-MAR PMID[20828184]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. root n.a. PMID[24317429]
NPO6333 Annona glabra Species Annonaceae Eukaryota fruits n.a. n.a. PMID[25499882]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. n.a. n.a. PMID[38415909]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. PMID[9584397]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. PMID[9599260]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO6333 Annona glabra Species Annonaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO20441 Glaucium flavum Species Papaveraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO6333 Annona glabra Species Annonaceae 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
NPO20441 Glaucium flavum n.a. n.a. 2.4 n.a. n.a. % PMID[38415909]
NPO20441 Glaucium flavum n.a. n.a. 1.4 n.a. n.a. % PMID[38415909]
NPO20441 Glaucium flavum n.a. n.a. 0.1 n.a. n.a. % PMID[38415909]
NPO20441 Glaucium flavum n.a. n.a. 0.42 n.a. n.a. % PMID[38415909]
NPO20441 Glaucium flavum n.a. n.a. 0.21 n.a. n.a. % PMID[38415909]
NPO20441 Glaucium flavum n.a. n.a. 10.69 n.a. n.a. % PMID[38415909]

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

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 NPC476571 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 NPC147390
1.0 High Similarity NPC428
0.8269 Intermediate Similarity NPC135538
0.8269 Intermediate Similarity NPC24233
0.7925 Intermediate Similarity NPC321505
0.7925 Intermediate Similarity NPC179825
0.7015 Intermediate Similarity NPC600872
0.6984 Remote Similarity NPC480592
0.6786 Remote Similarity NPC191376
0.6769 Remote Similarity NPC603603
0.6667 Remote Similarity NPC240841
0.6286 Remote Similarity NPC286119
0.6176 Remote Similarity NPC610959
0.6 Remote Similarity NPC314682
0.5915 Remote Similarity NPC609914
0.5893 Remote Similarity NPC213206
0.5893 Remote Similarity NPC188163
0.5893 Remote Similarity NPC328750
0.5867 Remote Similarity NPC601489
0.5867 Remote Similarity NPC604804
0.5862 Remote Similarity NPC88249
0.5862 Remote Similarity NPC185838
0.5806 Remote Similarity NPC249797
0.5806 Remote Similarity NPC193949
0.5763 Remote Similarity NPC609731
0.5714 Remote Similarity NPC295691
0.5714 Remote Similarity NPC207757
0.5714 Remote Similarity NPC54379
0.5645 Remote Similarity NPC189266
0.5645 Remote Similarity NPC2413
0.5645 Remote Similarity NPC110416
0.5606 Remote Similarity NPC317272
0.5606 Remote Similarity NPC268503
0.5556 Remote Similarity NPC104196
0.5455 Remote Similarity NPC192768
0.541 Remote Similarity NPC103379
0.5362 Remote Similarity NPC256012
0.5362 Remote Similarity NPC610965
0.5263 Remote Similarity NPC34559
0.5217 Remote Similarity NPC232514
0.52 Remote Similarity NPC311973
0.52 Remote Similarity NPC239824
0.5135 Remote Similarity NPC290582
0.5135 Remote Similarity NPC217748
0.5135 Remote Similarity NPC182052
0.5135 Remote Similarity NPC271013
0.5135 Remote Similarity NPC42663
0.5135 Remote Similarity NPC15414
0.5132 Remote Similarity NPC254441
0.5082 Remote Similarity NPC220858
0.5077 Remote Similarity NPC247639
0.5077 Remote Similarity NPC212794
0.5077 Remote Similarity NPC25084
0.5067 Remote Similarity NPC279228

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC476571 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
0.65 Remote Similarity NPD4010 Discontinued
0.5893 Remote Similarity NPD4664 Clinical (unspecified phase)

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