Natural Product: NPC16667

Natural Product IDNPC16667
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Tardioxopiperazine A
IUPAC Name (3S,6S)-3-methyl-6-[[2-(2-methylbut-3-en-2-yl)-5-(3-methylbut-2-enyl)-1H-indol-3-yl]methyl]piperazine-2,5-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL400852
PubChem CID 10810596
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000264] Organic acids and derivatives
      • [CHEMONTID:0000265] Carboxylic acids and derivatives
        • [CHEMONTID:0000013] Amino acids, peptides, and analogues
          • [CHEMONTID:0000347] Amino acids and derivatives
            • [CHEMONTID:0000060] Alpha amino acids and derivatives

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 WXGWEFVOPYZZTA-YWZLYKJASA-N
Standard InCHI InChI=1S/C24H31N3O2/c1-7-24(5,6)21-18(13-20-23(29)25-15(4)22(28)27-20)17-12-16(9-8-14(2)3)10-11-19(17)26-21/h7-8,10-12,15,20,26H,1,9,13H2,2-6H3,(H,25,29)(H,27,28)/t15-,20-/m0/s1
SMILES C=CC(c1[nH]c2c(c1C[C@@H]1N=C(O)[C@@H](N=C1O)C)cc(cc2)CC=C(C)C)(C)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   393.24 Volume:   427.47
?
Van der Waals volume.
Dense:   0.92 LogP:   3.993
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   3.031
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -4.456
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The logarithm of aqueous solubility value.
Rotatable Bonds:   6.0 Rigid Bonds:   18.0
TPSA:   80.97
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   3.0 Rings:   3.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.577 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.358 Fsp3:   0.417
MCE-18:   68.588
?
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:   0.809 Fluc inhibitor:   0.082
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.769
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.732
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.009 Promiscuous compounds:   0.459

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.846 MDCK Permeability:   -4.72
Pgp-inhibitor:   0.766 Pgp-substrate:   0.965
PAMPA:   0.157
?
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):   0.08
20% Bioavailability (F20%):   1.0 30% Bioavailability (F30%):   1.0
50% Bioavailability (F50%):   1.0

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.0 MRP1:   0.96
Plasma Protein Binding (PPB):   83.578% Volume Distribution (VD):   0.352
Fu: 16.881%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.996
OATP1B3 inhibitor:   0.984 BCRP inhibitor:   0.991
BSEP inhibitor:   0.929

ADMET: Metabolism

CYP1A2-inhibitor:   0.115 CYP1A2-substrate:   0.907
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.999
CYP2C9-inhibitor:   1.0 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.001 CYP2D6-substrate:   0.027
CYP3A4-inhibitor:   1.0 CYP3A4-substrate:   0.334
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.999
HLM stability:   1.0
?
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):  2.582 Half-life (T1/2):  1.393

ADMET: Toxicity

hERG Blockers:  0.03 hERG Blockers (10um):  0.079
Human Hepatotoxicity (H-HT):  1.0 Drug-induced Liver Injury (DILI):  0.995
AMES Toxicity:  0.162 Rat Oral Acute Toxicity:  0.783
Maximum Recommended Daily Dose:  0.554 Skin Sensitization:  1.0
Carcinogencity:  0.257 Eye Corrosion:  0.0
Eye Irritation:  0.501 Respiratory Toxicity:  0.901
Drug-induced Neurotoxicity:  0.504 Ototoxicity:  0.946
Hematotoxicity:  0.319 Drug-induced Nephrotoxicity:  0.951
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.005
A549 Cytotoxicity:  0.003 Hek293 Cytotoxicity:  0.048
BCF:   1.576
?
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:   4.381
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.783
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   5.319
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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
NPO31540 Aspergillus variecolor Species Aspergillaceae Eukaryota n.a. n.a. n.a. DOI[10.1021/jo00010a040]
NPO31540 Aspergillus variecolor Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[17896816]
NPO31540 Aspergillus variecolor Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[17965475]
NPO32843 eurotium cristatum en-220 Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[22727636]
NPO10055 Stichoneuron caudatum Species Stemonaceae Eukaryota n.a. n.a. n.a. PMID[24606395]
NPO32640 eurotium rubrum ma-150 Species Aspergillaceae Eukaryota Fungus Obtained from Marine Mangrove-Derived Rhizospheric Soil. n.a. n.a. PMID[25730346]
NPO10055 Stichoneuron caudatum Species Stemonaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO1387 Lactarius violascens Species Russulaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO4946 Antidesma venosum Species Phyllanthaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO31540 Aspergillus variecolor Species Aspergillaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO6189 Rhamnus nipalensis Species Rhamnaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO1387 Lactarius violascens Species Russulaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO8748 Dacrydium nidulum Species Podocarpaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO10055 Stichoneuron caudatum Species Stemonaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO6417 Lecanora grumosa Species Lecanoraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO6874 Desmodium floribundum Species Fabaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO11458 Hymenoxys subintegra Species Asteraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO7499 Mammillaria krameri Species Cactaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO4946 Antidesma venosum Species Phyllanthaceae 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
NPT19 Organism Escherichia coli Escherichia coli MIC = 64.0 ug.mL-1 PMID[22727636]
NPT16 Organism Staphylococcus aureus Staphylococcus aureus MIC = 8.0 ug.mL-1 PMID[22727636]

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 NPC16667 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
0.7385 Intermediate Similarity NPC67056
0.7164 Intermediate Similarity NPC280548
0.6984 Remote Similarity NPC285469
0.6479 Remote Similarity NPC38736
0.6027 Remote Similarity NPC470508
0.5676 Remote Similarity NPC472586
0.5316 Remote Similarity NPC473320
0.519 Remote Similarity NPC6982
0.5185 Remote Similarity NPC192270
0.5125 Remote Similarity NPC34508
0.5063 Remote Similarity NPC271734
0.5062 Remote Similarity NPC288785

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC16667 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