Natural Product: NPC604675

Natural Product IDNPC604675
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 GRTOGORTSDXSFK-XIEZEKGWSA-N
IUPAC Name n.a.
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL2079609
PubChem CID n.a.
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0001786] Yohimbine 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 GRTOGORTSDXSFK-XIEZEKGWSA-N
Standard InCHI InChI=1S/C21H24N2O3/c1-12-16-10-23-8-7-14-13-5-3-4-6-18(13)22-20(14)19(23)9-15(16)17(11-26-12)21(24)25-2/h3-6,11-12,15-16,19,22H,7-10H2,1-2H3/t12-,15+,16-,19+/m1/s1
SMILES COC(=O)C1=CO[C@H](C)[C@H]2CN3CCc4c([nH]c5ccccc45)[C@@H]3C[C@H]12

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   352.18 Volume:   361.535
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Van der Waals volume.
Dense:   0.974 LogP:   2.5
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.504
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.453
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The logarithm of aqueous solubility value.
Rotatable Bonds:   2.0 Rigid Bonds:   26.0
TPSA:   54.56
?
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:   0.801 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.936 Fsp3:   0.476
MCE-18:   91.419
?
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:   0.284 Fluc inhibitor:   0.233
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.556
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.106
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.002 Promiscuous compounds:   0.522

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.832 MDCK Permeability:   -4.824
Pgp-inhibitor:   0.229 Pgp-substrate:   0.82
PAMPA:   0.005
?
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):   0.0
20% Bioavailability (F20%):   0.61 30% Bioavailability (F30%):   0.897
50% Bioavailability (F50%):   0.988

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.934 MRP1:   1.0
Plasma Protein Binding (PPB):   84.423% Volume Distribution (VD):   0.538
Fu: 16.605%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.45
OATP1B3 inhibitor:   0.597 BCRP inhibitor:   0.973
BSEP inhibitor:   0.998

ADMET: Metabolism

CYP1A2-inhibitor:   0.906 CYP1A2-substrate:   0.237
CYP2C19-inhibitor:   0.741 CYP2C19-substrate:   0.019
CYP2C9-inhibitor:   0.0 CYP2C9-substrate:   0.976
CYP2D6-inhibitor:   0.003 CYP2D6-substrate:   0.557
CYP3A4-inhibitor:   1.0 CYP3A4-substrate:   1.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.958
HLM stability:   0.003
?
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):  10.756 Half-life (T1/2):  1.707

ADMET: Toxicity

hERG Blockers:  0.567 hERG Blockers (10um):  0.627
Human Hepatotoxicity (H-HT):  0.605 Drug-induced Liver Injury (DILI):  0.722
AMES Toxicity:  0.79 Rat Oral Acute Toxicity:  0.848
Maximum Recommended Daily Dose:  0.976 Skin Sensitization:  0.907
Carcinogencity:  0.832 Eye Corrosion:  0.0
Eye Irritation:  0.279 Respiratory Toxicity:  0.95
Drug-induced Neurotoxicity:  0.846 Ototoxicity:  0.421
Hematotoxicity:  0.274 Drug-induced Nephrotoxicity:  0.87
Genotoxicity:  0.994 RPMI-8226 Immunitoxicity:  0.054
A549 Cytotoxicity:  0.45 Hek293 Cytotoxicity:  0.559
BCF:   1.126
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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:   3.787
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.127
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.638
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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
NPO17362 Alstonia yunnanensis Species Apocynaceae Eukaryota n.a. n.a. n.a. PMID[19775092]
NPO53340 Uncaria elliptica R.Br.ex G.Don. Genus Rubiaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO17362 Alstonia yunnanensis Species Apocynaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO17362 Alstonia yunnanensis Species Apocynaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO17362 Alstonia yunnanensis Species Apocynaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO17362 Alstonia yunnanensis Species Apocynaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO17362 Alstonia yunnanensis Species Apocynaceae 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
NPT110 Individual protein Cytochrome P450 2D6 Homo sapiens Ki = 17.0 nM PMID[8487254]

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 NPC604675 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 NPC312870
1.0 High Similarity NPC199851
1.0 High Similarity NPC294909
1.0 High Similarity NPC254240
1.0 High Similarity NPC128265
0.7949 Intermediate Similarity NPC603895
0.7848 Intermediate Similarity NPC21638
0.7763 Intermediate Similarity NPC486449
0.7763 Intermediate Similarity NPC63199
0.7763 Intermediate Similarity NPC111602
0.7763 Intermediate Similarity NPC102338
0.7763 Intermediate Similarity NPC196251
0.7532 Intermediate Similarity NPC273374
0.6585 Remote Similarity NPC107782
0.6585 Remote Similarity NPC486454
0.6071 Remote Similarity NPC486443
0.6071 Remote Similarity NPC486446
0.6 Remote Similarity NPC175474
0.6 Remote Similarity NPC99921
0.5952 Remote Similarity NPC486452
0.5952 Remote Similarity NPC74591
0.593 Remote Similarity NPC100898
0.593 Remote Similarity NPC148183
0.593 Remote Similarity NPC21084
0.593 Remote Similarity NPC152768
0.593 Remote Similarity NPC605270
0.5833 Remote Similarity NPC220151
0.5833 Remote Similarity NPC19692
0.5795 Remote Similarity NPC293861
0.5747 Remote Similarity NPC131260
0.57 Remote Similarity NPC486444
0.57 Remote Similarity NPC649
0.5698 Remote Similarity NPC313985
0.5698 Remote Similarity NPC249150
0.5698 Remote Similarity NPC33619
0.5632 Remote Similarity NPC81654
0.5625 Remote Similarity NPC21174
0.5422 Remote Similarity NPC474897
0.5366 Remote Similarity NPC185200
0.5366 Remote Similarity NPC229173
0.52 Remote Similarity NPC191489
0.5192 Remote Similarity NPC199607
0.5192 Remote Similarity NPC54591
0.5169 Remote Similarity NPC483467
0.5059 Remote Similarity NPC165441

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC604675 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
1.0 High Similarity NPD4500 Approved
1.0 High Similarity NPD4501 Approved
0.5698 Remote Similarity NPD4601 Phase 4
0.5632 Remote Similarity NPD4600 Approved
0.52 Remote Similarity NPD7708 Phase 4

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