Natural Product: NPC11126

Natural Product IDNPC11126
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 (3S,6S)-3-(1H-Indol-3-Ylmethyl)-1,6-Dimethylpiperazine-2,5-Dione
IUPAC Name (3S,6S)-3-(1H-indol-3-ylmethyl)-1,6-dimethylpiperazine-2,5-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL2207535
PubChem CID 71463201
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 SSFZVWKVKADKHZ-ZANVPECISA-N
Standard InCHI InChI=1S/C15H17N3O2/c1-9-14(19)17-13(15(20)18(9)2)7-10-8-16-12-6-4-3-5-11(10)12/h3-6,8-9,13,16H,7H2,1-2H3,(H,17,19)/t9-,13-/m0/s1
SMILES OC1=N[C@@H](Cc2c[nH]c3c2cccc3)C(=O)N([C@H]1C)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   271.13 Volume:   277.079
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Van der Waals volume.
Dense:   0.979 LogP:   0.302
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.036
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.07
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The logarithm of aqueous solubility value.
Rotatable Bonds:   2.0 Rigid Bonds:   17.0
TPSA:   68.69
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Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   2.0 Rings:   3.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.876 GASA:   1.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.504 Fsp3:   0.333
MCE-18:   54.4
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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:   0.266 Fluc inhibitor:   0.127
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The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.114
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.216
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.008 Promiscuous compounds:   0.651

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.8 MDCK Permeability:   -4.504
Pgp-inhibitor:   0.781 Pgp-substrate:   0.999
PAMPA:   0.546
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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):   0.133
20% Bioavailability (F20%):   0.995 30% Bioavailability (F30%):   0.996
50% Bioavailability (F50%):   0.999

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.011 MRP1:   0.766
Plasma Protein Binding (PPB):   47.615% Volume Distribution (VD):   -0.034
Fu: 53.0%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.973
OATP1B3 inhibitor:   0.561 BCRP inhibitor:   0.55
BSEP inhibitor:   0.96

ADMET: Metabolism

CYP1A2-inhibitor:   0.92 CYP1A2-substrate:   0.558
CYP2C19-inhibitor:   0.999 CYP2C19-substrate:   0.055
CYP2C9-inhibitor:   0.996 CYP2C9-substrate:   0.003
CYP2D6-inhibitor:   0.132 CYP2D6-substrate:   0.769
CYP3A4-inhibitor:   0.999 CYP3A4-substrate:   0.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.491
HLM stability:   0.177
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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):  6.299 Half-life (T1/2):  1.369

ADMET: Toxicity

hERG Blockers:  0.013 hERG Blockers (10um):  0.046
Human Hepatotoxicity (H-HT):  1.0 Drug-induced Liver Injury (DILI):  0.994
AMES Toxicity:  0.524 Rat Oral Acute Toxicity:  0.63
Maximum Recommended Daily Dose:  0.368 Skin Sensitization:  0.999
Carcinogencity:  0.598 Eye Corrosion:  0.001
Eye Irritation:  0.814 Respiratory Toxicity:  0.749
Drug-induced Neurotoxicity:  0.378 Ototoxicity:  0.789
Hematotoxicity:  0.808 Drug-induced Nephrotoxicity:  0.924
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.01
A549 Cytotoxicity:  0.001 Hek293 Cytotoxicity:  0.016
BCF:   0.489
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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:   3.142
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.525
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.91
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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
NPO32990 acrostalagmus luteoalbus scsio f457 Species Plectosphaerellaceae Eukaryota n.a. n.a. n.a. PMID[23079524]

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
NPT65 Cell line HepG2 Homo sapiens IC50 > 100000.0 nM PMID[24901800]
NPT397 Cell line NCI-H460 Homo sapiens IC50 > 100000.0 nM PMID[23691978]
NPT83 Cell line MCF7 Homo sapiens IC50 > 100000.0 nM Open TG-GATES in vivo data: Biochemistry
NPT395 Cell line SF-268 Homo sapiens IC50 > 100000.0 nM PMID[21742496]

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 NPC11126 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
0.8103 Intermediate Similarity NPC228835
0.7097 Intermediate Similarity NPC17059
0.6364 Remote Similarity NPC59269
0.6102 Remote Similarity NPC282231
0.5873 Remote Similarity NPC49954
0.5833 Remote Similarity NPC480549
0.5645 Remote Similarity NPC63751
0.5645 Remote Similarity NPC279918
0.5556 Remote Similarity NPC54988
0.5556 Remote Similarity NPC480548
0.5424 Remote Similarity NPC190296
0.5366 Remote Similarity NPC489625
0.5294 Remote Similarity NPC470499
0.5224 Remote Similarity NPC192615
0.5211 Remote Similarity NPC160105
0.5161 Remote Similarity NPC608269
0.5152 Remote Similarity NPC605381
0.5082 Remote Similarity NPC480551
0.5079 Remote Similarity NPC267885
0.5075 Remote Similarity NPC611116

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC11126 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
0.5278 Remote Similarity NPD4184 Phase 2
0.5275 Remote Similarity NPD8405 Pre-clinical
0.5139 Remote Similarity NPD6595 Phase 4
0.5068 Remote Similarity NPD4862 Clinical (unspecified phase)
0.5059 Remote Similarity NPD7619 Phase 3

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