Natural Product: NPC63751

Natural Product IDNPC63751
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-Benzyl-6-(1H-Indol-3-Ylmethyl)Piperazine-2,5-Dione
IUPAC Name (3S,6S)-3-benzyl-6-(1H-indol-3-ylmethyl)piperazine-2,5-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL190059
PubChem CID 7408486
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 CUVKAUWOMPJEMI-ROUUACIJSA-N
Standard InCHI InChI=1S/C20H19N3O2/c24-19-17(10-13-6-2-1-3-7-13)22-20(25)18(23-19)11-14-12-21-16-9-5-4-8-15(14)16/h1-9,12,17-18,21H,10-11H2,(H,22,25)(H,23,24)/t17-,18-/m0/s1
SMILES OC1=N[C@@H](Cc2ccccc2)C(=N[C@H]1Cc1c[nH]c2c1cccc2)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   333.15 Volume:   347.093
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Van der Waals volume.
Dense:   0.96 LogP:   1.924
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.834
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.983
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The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   22.0
TPSA:   80.97
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Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   3.0 Rings:   4.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.681 GASA:   1.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.427 Fsp3:   0.2
MCE-18:   63.333
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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:   0.601 Fluc inhibitor:   0.258
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The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.183
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.415
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.043 Promiscuous compounds:   0.504

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.888 MDCK Permeability:   -4.656
Pgp-inhibitor:   0.785 Pgp-substrate:   0.781
PAMPA:   0.417
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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):   0.233
20% Bioavailability (F20%):   0.877 30% Bioavailability (F30%):   0.984
50% Bioavailability (F50%):   0.995

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.147 MRP1:   0.317
Plasma Protein Binding (PPB):   86.772% Volume Distribution (VD):   -0.088
Fu: 14.633%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.892
OATP1B3 inhibitor:   0.802 BCRP inhibitor:   0.63
BSEP inhibitor:   0.946

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.932
CYP2C19-inhibitor:   0.081 CYP2C19-substrate:   0.996
CYP2C9-inhibitor:   0.741 CYP2C9-substrate:   0.009
CYP2D6-inhibitor:   0.307 CYP2D6-substrate:   0.991
CYP3A4-inhibitor:   0.993 CYP3A4-substrate:   0.002
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.096
HLM stability:   0.998
?
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):  4.708 Half-life (T1/2):  1.128

ADMET: Toxicity

hERG Blockers:  0.094 hERG Blockers (10um):  0.093
Human Hepatotoxicity (H-HT):  1.0 Drug-induced Liver Injury (DILI):  0.996
AMES Toxicity:  0.156 Rat Oral Acute Toxicity:  0.874
Maximum Recommended Daily Dose:  0.852 Skin Sensitization:  1.0
Carcinogencity:  0.041 Eye Corrosion:  0.0
Eye Irritation:  0.435 Respiratory Toxicity:  0.788
Drug-induced Neurotoxicity:  0.512 Ototoxicity:  0.787
Hematotoxicity:  0.693 Drug-induced Nephrotoxicity:  0.994
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.004
A549 Cytotoxicity:  0.0 Hek293 Cytotoxicity:  0.035
BCF:   0.902
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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:   3.654
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.568
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.278
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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
NPO31451 Aspergillus sydowii Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[18505285]
NPO31451 Aspergillus sydowii Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[21718031]
NPO31451 Aspergillus sydowii Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[23647825]
NPO31451 Aspergillus sydowii Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[24057165]
NPO31451 Aspergillus sydowii Species Aspergillaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]

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
NPT135 Individual protein Chromobox protein homolog 1 Homo sapiens Potency n.a. 70794.6 nM PubChem BioAssay data set
NPT160 Individual protein TAR DNA-binding protein 43 Homo sapiens Potency n.a. 6309.6 nM PubChem BioAssay data set
NPT3579 Individual protein Calpain 1 Homo sapiens Inhibition = 0.0 % PMID[15896956]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT111 Cell line K562 Homo sapiens IC50 > 100000.0 nM PMID[22617493]
NPT179 Cell line A2780 Homo sapiens IC50 > 100000.0 nM PMID[22617493]

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 NPC63751 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
0.8511 High Similarity NPC59269
0.8 Intermediate Similarity NPC192615
0.7692 Intermediate Similarity NPC282231
0.7321 Intermediate Similarity NPC49954
0.7273 Intermediate Similarity NPC54988
0.6786 Remote Similarity NPC279918
0.6714 Remote Similarity NPC487314
0.6154 Remote Similarity NPC160105
0.6081 Remote Similarity NPC193761
0.6 Remote Similarity NPC486528
0.5769 Remote Similarity NPC487596
0.5645 Remote Similarity NPC11126
0.5532 Remote Similarity NPC311242
0.5529 Remote Similarity NPC31385
0.5439 Remote Similarity NPC190296
0.5405 Remote Similarity NPC314603
0.5402 Remote Similarity NPC110602
0.5402 Remote Similarity NPC479071
0.5352 Remote Similarity NPC145333
0.5281 Remote Similarity NPC479075
0.5263 Remote Similarity NPC34779
0.5227 Remote Similarity NPC54420
0.5224 Remote Similarity NPC228835
0.52 Remote Similarity NPC601214
0.5165 Remote Similarity NPC479065
0.5147 Remote Similarity NPC17059
0.5109 Remote Similarity NPC479073
0.5094 Remote Similarity NPC279081
0.5082 Remote Similarity NPC267885
0.5075 Remote Similarity NPC478795
0.5054 Remote Similarity NPC479076

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC63751 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
0.6026 Remote Similarity NPD8110 Clinical (unspecified phase)
0.5821 Remote Similarity NPD6595 Phase 4
0.5802 Remote Similarity NPD7948 Phase 1
0.5732 Remote Similarity NPD8431 Pre-clinical
0.5507 Remote Similarity NPD4184 Phase 2
0.5341 Remote Similarity NPD8458 Clinical (unspecified phase)
0.5281 Remote Similarity NPD8405 Pre-clinical
0.507 Remote Similarity NPD4862 Clinical (unspecified phase)
0.5059 Remote Similarity NPD7594 Clinical (unspecified phase)

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