Natural Product: NPC81079

Natural Product IDNPC81079
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Aplysinamisine I
IUPAC Name (5S,6R)-N-[(Z)-3-(2-amino-1H-imidazol-5-yl)prop-2-enyl]-7,9-dibromo-6-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,7,9-triene-3-carboxamide
Synonyms Aplysinamisine I
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL517447
PubChem CID 23427561
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000002] Organoheterocyclic compounds
      • [CHEMONTID:0000436] Azoles
        • [CHEMONTID:0000078] Imidazoles
          • [CHEMONTID:0002310] Substituted imidazoles
            • [CHEMONTID:0001225] Aminoimidazoles

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 RPBHRSIJJYCYKG-PDUXPGBHSA-N
Standard InCHI InChI=1S/C16H17Br2N5O4/c1-26-12-9(17)5-16(13(24)11(12)18)6-10(23-27-16)14(25)20-4-2-3-8-7-21-15(19)22-8/h2-3,5,7,13,24H,4,6H2,1H3,(H,20,25)(H3,19,21,22)/b3-2-/t13-,16+/m0/s1
SMILES COC1=C(Br)[C@@H]([C@]2(C=C1Br)ON=C(C2)C(=O)NC/C=Cc1c[nH]c(=N)[nH]1)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   500.96 Volume:   369.88
?
Van der Waals volume.
Dense:   1.354 LogP:   1.435
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.801
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.273
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   6.0 Rigid Bonds:   19.0
TPSA:   135.58
?
Topological Polar Surface Area.
 H-Bond Acceptor:   9.0
H-Bond Donor:   5.0 Rings:   3.0
Heavy Atoms:   11.0

MedChem Properties

QED Drug-Likeness Score:   0.415 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   5.291 Fsp3:   0.312
MCE-18:   85.714
?
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:   Accepted
Golden Triangle Rule:   Accepted BMS Rule:   0
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.802 Fluc inhibitor:   0.066
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.228
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.53
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.079 Promiscuous compounds:   0.223

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.875 MDCK Permeability:   -5.07
Pgp-inhibitor:   0.054 Pgp-substrate:   0.164
PAMPA:   0.239
?
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):   0.013
20% Bioavailability (F20%):   0.235 30% Bioavailability (F30%):   0.933
50% Bioavailability (F50%):   0.965

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.195 MRP1:   0.988
Plasma Protein Binding (PPB):   91.734% Volume Distribution (VD):   0.02
Fu: 8.306%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.981
OATP1B3 inhibitor:   0.953 BCRP inhibitor:   0.756
BSEP inhibitor:   0.887

ADMET: Metabolism

CYP1A2-inhibitor:   0.179 CYP1A2-substrate:   0.003
CYP2C19-inhibitor:   0.0 CYP2C19-substrate:   0.033
CYP2C9-inhibitor:   0.0 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.0 CYP2D6-substrate:   0.017
CYP3A4-inhibitor:   0.001 CYP3A4-substrate:   0.021
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.227
HLM stability:   0.481
?
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):  1.407 Half-life (T1/2):  2.46

ADMET: Toxicity

hERG Blockers:  0.277 hERG Blockers (10um):  0.505
Human Hepatotoxicity (H-HT):  0.99 Drug-induced Liver Injury (DILI):  0.897
AMES Toxicity:  0.991 Rat Oral Acute Toxicity:  0.974
Maximum Recommended Daily Dose:  0.891 Skin Sensitization:  1.0
Carcinogencity:  0.998 Eye Corrosion:  0.0
Eye Irritation:  0.753 Respiratory Toxicity:  0.996
Drug-induced Neurotoxicity:  0.849 Ototoxicity:  0.506
Hematotoxicity:  0.034 Drug-induced Nephrotoxicity:  0.747
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.064
A549 Cytotoxicity:  0.531 Hek293 Cytotoxicity:  0.893
BCF:   0.849
?
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:   3.589
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.243
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.64
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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
NPO11745 Subergorgia suberosa Species Subergorgiidae Eukaryota n.a. Taiwanese gorgonian coral n.a. PMID[12088433]
NPO11745 Subergorgia suberosa Species Subergorgiidae Eukaryota n.a. Taiwanese Gorgonian coral n.a. PMID[12141868]
NPO11745 Subergorgia suberosa Species Subergorgiidae Eukaryota n.a. n.a. n.a. PMID[16124781]
NPO11745 Subergorgia suberosa Species Subergorgiidae Eukaryota n.a. n.a. n.a. PMID[18290631]
NPO211 Aplysina cauliformis Species Aplysinidae Eukaryota n.a. n.a. n.a. PMID[8350091]
NPO211 Aplysina cauliformis Species Aplysinidae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO11745 Subergorgia suberosa Species Subergorgiidae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO11870 Rhododendron arboreum Species Ericaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO11870 Rhododendron arboreum Species Ericaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO211 Aplysina cauliformis Species Aplysinidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO11745 Subergorgia suberosa Species Subergorgiidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO11870 Rhododendron arboreum Species Ericaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO12594 Hybanthus enneaspermus Species Violaceae 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

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT83 Cell line MCF7 Homo sapiens IC50 > 50.0 ug.mL-1 PMID[8350091]
NPT404 Cell line CCRF-CEM Homo sapiens IC50 > 50.0 ug.mL-1 PMID[8350091]
NPT393 Cell line HCT-116 Homo sapiens IC50 = 10.0 ug.mL-1 PMID[8350091]

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 NPC81079 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
0.75 Intermediate Similarity NPC304257
0.7297 Intermediate Similarity NPC181086
0.6471 Remote Similarity NPC1702
0.6286 Remote Similarity NPC158672
0.6076 Remote Similarity NPC600759
0.6027 Remote Similarity NPC487917
0.5926 Remote Similarity NPC201900
0.5844 Remote Similarity NPC473262
0.5844 Remote Similarity NPC202166
0.5783 Remote Similarity NPC608121
0.5696 Remote Similarity NPC473261
0.5696 Remote Similarity NPC300912
0.5692 Remote Similarity NPC30521
0.55 Remote Similarity NPC145149
0.5488 Remote Similarity NPC487872
0.5488 Remote Similarity NPC608122
0.5432 Remote Similarity NPC313173
0.5366 Remote Similarity NPC260270
0.5301 Remote Similarity NPC470886
0.5294 Remote Similarity NPC185172
0.5294 Remote Similarity NPC487873
0.5238 Remote Similarity NPC66855
0.5227 Remote Similarity NPC487915
0.5185 Remote Similarity NPC289324
0.5176 Remote Similarity NPC130714
0.5057 Remote Similarity NPC477220

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC81079 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