Natural Product: NPC130714

Natural Product IDNPC130714
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Aplysinone C
IUPAC Name (1'R,5S,6'S)-3'-bromo-N-[5-[[(5S,6R)-7,9-dibromo-6-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,7,9-triene-3-carbonyl]amino]pentyl]-2'-oxospiro[4H-1,2-oxazole-5,5'-7-oxabicyclo[4.1.0]hept-3-ene]-3-carboxamide
Synonyms Aplysinone C
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL229729
PubChem CID 44424474
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0004603] Organic oxygen compounds
      • [CHEMONTID:0000323] Organooxygen compounds
        • [CHEMONTID:0001831] Carbonyl compounds
          • [CHEMONTID:0000118] Ketones
            • [CHEMONTID:0003487] Cyclic ketones
              • [CHEMONTID:0004325] Cyclohexenones

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 GSUVKSRKZPOPBP-DRRHGHKVSA-N
Standard InCHI InChI=1S/C24H25Br3N4O8/c1-36-17-12(26)8-23(19(33)15(17)27)9-13(30-38-23)21(34)28-5-3-2-4-6-29-22(35)14-10-24(39-31-14)7-11(25)16(32)18-20(24)37-18/h7-8,18-20,33H,2-6,9-10H2,1H3,(H,28,34)(H,29,35)/t18-,19-,20-,23+,24+/m0/s1
SMILES COC1=C(Br)[C@@H]([C@]2(C=C1Br)ON=C(C2)C(=O)NCCCCCNC(=O)C1=NO[C@@]2(C1)C=C(Br)C(=O)[C@H]1[C@@H]2O1)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   733.92 Volume:   531.946
?
Van der Waals volume.
Dense:   1.38 LogP:   2.957
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.918
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -4.738
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   11.0 Rigid Bonds:   27.0
TPSA:   160.44
?
Topological Polar Surface Area.
 H-Bond Acceptor:   12.0
H-Bond Donor:   3.0 Rings:   5.0
Heavy Atoms:   15.0

MedChem Properties

QED Drug-Likeness Score:   0.239 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   5.77 Fsp3:   0.542
MCE-18:   111.486
?
MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.
 Lipinski Rule-of-5:   Accepted
Pfizer Rule:   Rejected GSK Rule:   Accepted
Golden Triangle Rule:   Accepted BMS Rule:   0
Chelating Alert:   0 PAINS Alert:   1
Colloidal aggregators:   0.712 Fluc inhibitor:   0.016
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.108
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.555
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.102 Promiscuous compounds:   0.14

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.768 MDCK Permeability:   -4.622
Pgp-inhibitor:   0.067 Pgp-substrate:   0.121
PAMPA:   0.908
?
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):   0.204
20% Bioavailability (F20%):   0.895 30% Bioavailability (F30%):   0.985
50% Bioavailability (F50%):   0.987

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.018 MRP1:   0.99
Plasma Protein Binding (PPB):   97.119% Volume Distribution (VD):   -0.091
Fu: 1.937%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.998
OATP1B3 inhibitor:   0.996 BCRP inhibitor:   0.0
BSEP inhibitor:   0.974

ADMET: Metabolism

CYP1A2-inhibitor:   0.003 CYP1A2-substrate:   0.715
CYP2C19-inhibitor:   0.003 CYP2C19-substrate:   0.997
CYP2C9-inhibitor:   0.0 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.0 CYP2D6-substrate:   0.583
CYP3A4-inhibitor:   0.0 CYP3A4-substrate:   0.997
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.99
HLM stability:   0.94
?
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):  1.001 Half-life (T1/2):  3.47

ADMET: Toxicity

hERG Blockers:  0.018 hERG Blockers (10um):  0.069
Human Hepatotoxicity (H-HT):  0.548 Drug-induced Liver Injury (DILI):  0.999
AMES Toxicity:  1.0 Rat Oral Acute Toxicity:  0.99
Maximum Recommended Daily Dose:  0.991 Skin Sensitization:  1.0
Carcinogencity:  0.984 Eye Corrosion:  0.0
Eye Irritation:  0.126 Respiratory Toxicity:  0.858
Drug-induced Neurotoxicity:  0.952 Ototoxicity:  0.817
Hematotoxicity:  0.283 Drug-induced Nephrotoxicity:  0.958
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.13
A549 Cytotoxicity:  0.893 Hek293 Cytotoxicity:  0.922
BCF:   1.155
?
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:   4.103
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.704
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   5.231
?
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
NPO8996 Aplysina gerardogreeni Species Aplysinidae Eukaryota n.a. n.a. n.a. PMID[17512741]
NPO8996 Aplysina gerardogreeni Species Aplysinidae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO8996 Aplysina gerardogreeni Species Aplysinidae 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
NPT139 Cell line HT-29 Homo sapiens TGI > 10.0 ug.mL-1 PMID[17958396]
NPT82 Cell line MDA-MB-231 Homo sapiens GI50 = 5600.0 nM PMID[17958396]
NPT82 Cell line MDA-MB-231 Homo sapiens TGI = 5800.0 nM PMID[17958396]
NPT81 Cell line A549 Homo sapiens GI50 = 10700.0 nM PMID[17958396]
NPT81 Cell line A549 Homo sapiens TGI > 10.0 ug.mL-1 PMID[17958396]
NPT139 Cell line HT-29 Homo sapiens GI50 = 12600.0 nM PMID[17958396]

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 NPC130714 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
0.7727 Intermediate Similarity NPC158672
0.7164 Intermediate Similarity NPC1702
0.6933 Remote Similarity NPC473261
0.6933 Remote Similarity NPC300912
0.6456 Remote Similarity NPC470886
0.6447 Remote Similarity NPC473262
0.6447 Remote Similarity NPC202166
0.6329 Remote Similarity NPC260270
0.6216 Remote Similarity NPC487917
0.6076 Remote Similarity NPC145149
0.5783 Remote Similarity NPC66855
0.561 Remote Similarity NPC313173
0.5581 Remote Similarity NPC477220
0.5441 Remote Similarity NPC30521
0.5412 Remote Similarity NPC181086
0.5402 Remote Similarity NPC608121
0.5357 Remote Similarity NPC304257
0.5333 Remote Similarity NPC470892
0.5333 Remote Similarity NPC172626
0.519 Remote Similarity NPC473683
0.5176 Remote Similarity NPC81079
0.5172 Remote Similarity NPC201900
0.5116 Remote Similarity NPC487872
0.5116 Remote Similarity NPC600759
0.5116 Remote Similarity NPC608122
0.5054 Remote Similarity NPC601097

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC130714 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