Natural Product: NPC22476

Natural Product IDNPC22476
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 AEXBRBWRPNGGEZ-FKBYEOEOSA-N
IUPAC Name n.a.
Synonyms 1-Methoxytabersonine; 11-Methoxytabersonine
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL1165751
PubChem CID 443356
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0002672] Plumeran-type alkaloids

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 AEXBRBWRPNGGEZ-FKBYEOEOSA-N
Standard InCHI InChI=1S/C22H26N2O3/c1-4-21-8-5-10-24-11-9-22(20(21)24)16-7-6-14(26-2)12-17(16)23-18(22)15(13-21)19(25)27-3/h5-8,12,20,23H,4,9-11,13H2,1-3H3/t20-,21-,22-/m0/s1
SMILES COc1ccc2c(c1)NC1=C(C[C@]3([C@H]4[C@@]21CCN4CC=C3)CC)C(=O)OC

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   366.19 Volume:   378.831
?
Van der Waals volume.
Dense:   0.967 LogP:   2.859
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.881
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -4.122
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   24.0
TPSA:   50.8
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   1.0 Rings:   5.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.657 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.602 Fsp3:   0.5
MCE-18:   128.303
?
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:   0 PAINS Alert:   0
Colloidal aggregators:   0.086 Fluc inhibitor:   0.0
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.69
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.354
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.001 Promiscuous compounds:   0.025

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.924 MDCK Permeability:   -4.737
Pgp-inhibitor:   0.005 Pgp-substrate:   0.998
PAMPA:   0.003
?
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):   0.001
20% Bioavailability (F20%):   0.859 30% Bioavailability (F30%):   0.995
50% Bioavailability (F50%):   0.993

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.749 MRP1:   0.986
Plasma Protein Binding (PPB):   95.438% Volume Distribution (VD):   0.594
Fu: 3.772%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.14
OATP1B3 inhibitor:   0.084 BCRP inhibitor:   0.056
BSEP inhibitor:   0.788

ADMET: Metabolism

CYP1A2-inhibitor:   0.91 CYP1A2-substrate:   0.784
CYP2C19-inhibitor:   0.993 CYP2C19-substrate:   0.304
CYP2C9-inhibitor:   0.927 CYP2C9-substrate:   0.767
CYP2D6-inhibitor:   0.943 CYP2D6-substrate:   0.808
CYP3A4-inhibitor:   0.447 CYP3A4-substrate:   0.059
CYP2B6-substrate:   0.073 CYP2C8-inhibitor:   0.916
HLM stability:   0.977
?
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):  11.162 Half-life (T1/2):  1.162

ADMET: Toxicity

hERG Blockers:  0.266 hERG Blockers (10um):  0.395
Human Hepatotoxicity (H-HT):  0.662 Drug-induced Liver Injury (DILI):  0.595
AMES Toxicity:  0.391 Rat Oral Acute Toxicity:  0.631
Maximum Recommended Daily Dose:  0.838 Skin Sensitization:  0.804
Carcinogencity:  0.48 Eye Corrosion:  0.001
Eye Irritation:  0.214 Respiratory Toxicity:  0.955
Drug-induced Neurotoxicity:  0.831 Ototoxicity:  0.489
Hematotoxicity:  0.708 Drug-induced Nephrotoxicity:  0.884
Genotoxicity:  0.972 RPMI-8226 Immunitoxicity:  0.07
A549 Cytotoxicity:  0.256 Hek293 Cytotoxicity:  0.497
BCF:   1.262
?
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:   3.953
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.266
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.86
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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
NPO3298 Melodinus tenuicaudatus Species Apocynaceae Eukaryota n.a. n.a. n.a. PMID[20462230]
NPO33137 melodinus suaveolens Species Apocynaceae Eukaryota n.a. n.a. n.a. PMID[22260257]
NPO33137 melodinus suaveolens Species Apocynaceae Eukaryota n.a. n.a. n.a. PMID[24274642]
NPO3298 Melodinus tenuicaudatus Species Apocynaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3298 Melodinus tenuicaudatus Species Apocynaceae Eukaryota n.a. n.a. n.a. Database[TCMID]

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
NPT116 Cell line HL-60 Homo sapiens IC50 = 200.0 nM PMID[12828470]
NPT83 Cell line MCF7 Homo sapiens IC50 = 2100.0 nM PMID[19181524]
NPT660 Cell line SW480 Homo sapiens IC50 = 12700.0 nM DrugMatrix in vitro pharmacology data
NPT81 Cell line A549 Homo sapiens IC50 = 12800.0 nM PMID[22607668]
NPT659 Cell line SMMC-7721 Homo sapiens IC50 = 13100.0 nM PMID[22607668]
NPT116 Cell line HL-60 Homo sapiens IC50 = 500.0 nM PMID[22934671]
NPT659 Cell line SMMC-7721 Homo sapiens IC50 = 1100.0 nM PMID[12880316]
NPT81 Cell line A549 Homo sapiens IC50 = 1000.0 nM PMID[9514009]
NPT83 Cell line MCF7 Homo sapiens IC50 = 200.0 nM DOI[10.1007/s00044-012-0429-8]
NPT660 Cell line SW480 Homo sapiens IC50 = 2400.0 nM PMID[20621475]

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 NPC22476 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
0.8194 Intermediate Similarity NPC475147
0.8 Intermediate Similarity NPC87714
0.7867 Intermediate Similarity NPC475133
0.7808 Intermediate Similarity NPC123241
0.7763 Intermediate Similarity NPC119722
0.75 Intermediate Similarity NPC203628
0.6962 Remote Similarity NPC303214
0.6962 Remote Similarity NPC5630
0.679 Remote Similarity NPC232600
0.6707 Remote Similarity NPC189661
0.6071 Remote Similarity NPC186669
0.6064 Remote Similarity NPC77812
0.6064 Remote Similarity NPC303387
0.6 Remote Similarity NPC469722
0.5714 Remote Similarity NPC485928
0.5714 Remote Similarity NPC477068
0.5698 Remote Similarity NPC269449
0.5644 Remote Similarity NPC483959
0.5581 Remote Similarity NPC293458
0.5581 Remote Similarity NPC195636
0.5444 Remote Similarity NPC19175
0.5422 Remote Similarity NPC61013
0.5393 Remote Similarity NPC476069
0.5281 Remote Similarity NPC485981
0.5268 Remote Similarity NPC111877
0.5233 Remote Similarity NPC128948
0.5175 Remote Similarity NPC115588
0.5172 Remote Similarity NPC159963
0.5161 Remote Similarity NPC128476

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC22476 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