Natural Product: NPC216643

Natural Product IDNPC216643
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Sid124895033
IUPAC Name 3-[bis(1H-indol-3-yl)methyl]-1H-indole
Synonyms 1,1,1-Tris(3-Indolyl)Methane
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL522998
PubChem CID 254323
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000002] Organoheterocyclic compounds
      • [CHEMONTID:0000211] Indoles and derivatives
        • [CHEMONTID:0002497] Indoles
          • [CHEMONTID:0004196] 3-alkylindoles

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 AXZRNKFNIAOZEK-UHFFFAOYSA-N
Standard InCHI InChI=1S/C25H19N3/c1-4-10-22-16(7-1)19(13-26-22)25(20-14-27-23-11-5-2-8-17(20)23)21-15-28-24-12-6-3-9-18(21)24/h1-15,25-28H
SMILES c1ccc2c(c1)c(c[nH]2)C(c1c[nH]c2c1cccc2)c1c[nH]c2c1cccc2

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   361.16 Volume:   390.97
?
Van der Waals volume.
Dense:   0.924 LogP:   5.208
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   3.927
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -6.595
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The logarithm of aqueous solubility value.
Rotatable Bonds:   3.0 Rigid Bonds:   30.0
TPSA:   47.37
?
Topological Polar Surface Area.
 H-Bond Acceptor:   3.0
H-Bond Donor:   3.0 Rings:   6.0
Heavy Atoms:   3.0

MedChem Properties

QED Drug-Likeness Score:   0.331 GASA:   0.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   2.165 Fsp3:   0.04
MCE-18:   28.0
?
MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.
 Lipinski Rule-of-5:   Rejected
Pfizer Rule:   Accepted GSK Rule:   Accepted
Golden Triangle Rule:   Rejected BMS Rule:   0
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   1.0 Fluc inhibitor:   0.637
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.239
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.837
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.493 Promiscuous compounds:   0.604

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.945 MDCK Permeability:   -4.787
Pgp-inhibitor:   0.889 Pgp-substrate:   0.248
PAMPA:   0.055
?
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):   0.0
20% Bioavailability (F20%):   0.047 30% Bioavailability (F30%):   0.536
50% Bioavailability (F50%):   0.971

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.3 MRP1:   0.789
Plasma Protein Binding (PPB):   97.67% Volume Distribution (VD):   0.202
Fu: 1.63%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.984
OATP1B3 inhibitor:   0.991 BCRP inhibitor:   0.727
BSEP inhibitor:   1.0

ADMET: Metabolism

CYP1A2-inhibitor:   1.0 CYP1A2-substrate:   1.0
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   1.0
CYP2C9-inhibitor:   1.0 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.143 CYP2D6-substrate:   1.0
CYP3A4-inhibitor:   1.0 CYP3A4-substrate:   0.957
CYP2B6-substrate:   0.972 CYP2C8-inhibitor:   1.0
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):  8.943 Half-life (T1/2):  0.22

ADMET: Toxicity

hERG Blockers:  0.376 hERG Blockers (10um):  0.717
Human Hepatotoxicity (H-HT):  0.798 Drug-induced Liver Injury (DILI):  0.636
AMES Toxicity:  0.616 Rat Oral Acute Toxicity:  0.768
Maximum Recommended Daily Dose:  0.853 Skin Sensitization:  0.108
Carcinogencity:  0.477 Eye Corrosion:  0.0
Eye Irritation:  0.552 Respiratory Toxicity:  0.864
Drug-induced Neurotoxicity:  0.904 Ototoxicity:  0.642
Hematotoxicity:  0.381 Drug-induced Nephrotoxicity:  0.69
Genotoxicity:  0.799 RPMI-8226 Immunitoxicity:  0.06
A549 Cytotoxicity:  0.325 Hek293 Cytotoxicity:  0.43
BCF:   2.377
?
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:   4.618
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   6.31
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   6.783
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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
NPO11616 Vibrio parahaemolyticus Species Vibrionaceae Bacteria n.a. North Sea n.a. PMID[14640534]
NPO11616 Vibrio parahaemolyticus Species Vibrionaceae Bacteria n.a. n.a. n.a. PMID[7853008]
NPO11616 Vibrio parahaemolyticus Species Vibrionaceae Bacteria n.a. n.a. n.a. Database[COCONUT]
NPO11616 Vibrio parahaemolyticus Species Vibrionaceae Bacteria n.a. n.a. n.a. DOI[DOI: 10.1111/j.1574-6968.1992.tb05311.x]
NPO11616 Vibrio parahaemolyticus Species Vibrionaceae Bacteria 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
NPT154 Individual protein Mothers against decapentaplegic homolog 3 Homo sapiens Potency n.a. 10000.0 nM PMID[26819664]
NPT23071 Single protein G-protein coupled receptor 84 Homo sapiens EC50 > 10000.0 nM PMID[28406627]
NPT23071 Single protein G-protein coupled receptor 84 Homo sapiens Emax = -10.0 % PMID[28406627]
NPT23071 Single protein G-protein coupled receptor 84 Homo sapiens Emax = 10.0 % PMID[28406627]
NPT8 Individual protein DNA polymerase iota Homo sapiens Potency n.a. 100000.0 nM PubChem BioAssay data set

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT65 Cell line HepG2 Homo sapiens Potency n.a. 35481.3 nM PMID[15165138]
NPT172 Organism Proteus mirabilis Proteus mirabilis MIC = 250.0 ug.mL-1 PMID[21377877]
NPT2909 Organism Shigella flexneri Shigella flexneri MIC = 250.0 ug.mL-1 PMID[17696332]
NPT6 Organism Plasmodium falciparum Plasmodium falciparum Z score = 3.19 n.a. Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum ,using a nano luciferase reporter read-out
NPT6 Organism Plasmodium falciparum Plasmodium falciparum Inhibition = -27.0 % Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum ,using a nano luciferase reporter read-out
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. MIC = 125.0 ug.mL-1 DOI[10.1007/s00044-013-0737-7]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. MIC = 31.2 ug.mL-1 DOI[10.1007/s00044-013-0737-7]
NPT79 Organism Bacillus subtilis Bacillus subtilis MIC = 250.0 ug.mL-1 PMID[18177012]
NPT602 Organism Mycobacterium smegmatis Mycobacterium smegmatis MIC = 31.2 ug.mL-1 PMID[16949283]
NPT1826 Organism Lactococcus lactis Lactococcus lactis MIC = 500.0 ug.mL-1 PMID[17329108]
NPT16 Organism Staphylococcus aureus Staphylococcus aureus MIC = 250.0 ug.mL-1 PMID[18672864]
NPT19 Organism Escherichia coli Escherichia coli MIC = 125.0 ug.mL-1 PMID[16203143]
NPT18 Organism Pseudomonas aeruginosa Pseudomonas aeruginosa MIC = 125.0 ug.mL-1 PMID[10924160]

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 NPC216643 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
0.8 Intermediate Similarity NPC601179
0.6829 Remote Similarity NPC603226
0.6176 Remote Similarity NPC261195
0.6111 Remote Similarity NPC288838
0.6111 Remote Similarity NPC601214
0.5946 Remote Similarity NPC105127
0.5946 Remote Similarity NPC53947
0.5946 Remote Similarity NPC102423
0.5946 Remote Similarity NPC300149
0.5946 Remote Similarity NPC42372
0.5946 Remote Similarity NPC230002
0.575 Remote Similarity NPC29886
0.5641 Remote Similarity NPC131718
0.5641 Remote Similarity NPC96102
0.55 Remote Similarity NPC230869
0.55 Remote Similarity NPC138370
0.55 Remote Similarity NPC279081
0.5366 Remote Similarity NPC72435
0.5366 Remote Similarity NPC604154
0.5238 Remote Similarity NPC84911
0.5238 Remote Similarity NPC154339
0.5238 Remote Similarity NPC608908
0.5116 Remote Similarity NPC111275
0.5116 Remote Similarity NPC73767

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC216643 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
0.5641 Remote Similarity NPD198 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