Natural Product: NPC294693

Natural Product IDNPC294693
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Chetoseminudin B
IUPAC Name (3S,6S)-6-(hydroxymethyl)-3-(1H-indol-3-ylmethyl)-1-methyl-3,6-bis(methylsulfanyl)piperazine-2,5-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL512683
PubChem CID 11211175
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 CCPHAMSKHBDMDS-IRXDYDNUSA-N
Standard InCHI InChI=1S/C17H21N3O3S2/c1-20-15(23)16(24-2,19-14(22)17(20,10-21)25-3)8-11-9-18-13-7-5-4-6-12(11)13/h4-7,9,18,21H,8,10H2,1-3H3,(H,19,22)/t16-,17-/m0/s1
SMILES CN1C(=O)[C@@](Cc2c[nH]c3ccccc23)(N=C([C@]1(CO)SC)O)SC

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   379.1 Volume:   357.479
?
Van der Waals volume.
Dense:   1.06 LogP:   1.449
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.913
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.517
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   5.0 Rigid Bonds:   17.0
TPSA:   88.92
?
Topological Polar Surface Area.
 H-Bond Acceptor:   6.0
H-Bond Donor:   3.0 Rings:   3.0
Heavy Atoms:   8.0

MedChem Properties

QED Drug-Likeness Score:   0.741 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.347 Fsp3:   0.412
MCE-18:   66.5
?
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:   0.084 Fluc inhibitor:   0.0
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.106
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.078
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.62 Promiscuous compounds:   0.051

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.438 MDCK Permeability:   -4.85
Pgp-inhibitor:   0.514 Pgp-substrate:   0.778
PAMPA:   0.476
?
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):   0.516
20% Bioavailability (F20%):   0.582 30% Bioavailability (F30%):   0.907
50% Bioavailability (F50%):   0.972

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.173 MRP1:   0.695
Plasma Protein Binding (PPB):   87.481% Volume Distribution (VD):   -0.063
Fu: 9.452%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.756
OATP1B3 inhibitor:   0.731 BCRP inhibitor:   0.054
BSEP inhibitor:   0.619

ADMET: Metabolism

CYP1A2-inhibitor:   0.004 CYP1A2-substrate:   0.993
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.795
CYP2C9-inhibitor:   0.003 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.008 CYP2D6-substrate:   0.9
CYP3A4-inhibitor:   1.0 CYP3A4-substrate:   0.002
CYP2B6-substrate:   0.001 CYP2C8-inhibitor:   0.999
HLM stability:   0.954
?
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):  5.417 Half-life (T1/2):  0.777

ADMET: Toxicity

hERG Blockers:  0.001 hERG Blockers (10um):  0.012
Human Hepatotoxicity (H-HT):  1.0 Drug-induced Liver Injury (DILI):  0.997
AMES Toxicity:  0.881 Rat Oral Acute Toxicity:  0.855
Maximum Recommended Daily Dose:  0.029 Skin Sensitization:  1.0
Carcinogencity:  0.99 Eye Corrosion:  0.0
Eye Irritation:  0.403 Respiratory Toxicity:  0.679
Drug-induced Neurotoxicity:  0.032 Ototoxicity:  0.352
Hematotoxicity:  0.638 Drug-induced Nephrotoxicity:  0.997
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.004
A549 Cytotoxicity:  0.003 Hek293 Cytotoxicity:  0.26
BCF:   0.556
?
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:   3.28
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.594
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.022
?
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
NPO8658 Chaetomium seminudum Species Chaetomiaceae Eukaryota n.a. n.a. n.a. PMID[14738397]
NPO333 Nectria inventa Species Nectriaceae Eukaryota n.a. isolated from sediment collected by dredge at >600 m in the Monterey Bay trench n.a. PMID[20303767]
NPO32990 acrostalagmus luteoalbus scsio f457 Species Plectosphaerellaceae Eukaryota n.a. n.a. n.a. PMID[23079524]
NPO40284 Phaeosphaeria fuckelii Species Phaeosphaeriaceae Eukaryota n.a. n.a. n.a. PMID[32342692]
NPO8658 Chaetomium seminudum Species Chaetomiaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO40284 Phaeosphaeria fuckelii Species Phaeosphaeriaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO8658 Chaetomium seminudum Species Chaetomiaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO333 Nectria inventa Species Nectriaceae 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
NPT470 Individual protein Rhodesain Trypanosoma brucei rhodesiense IC50 > 50000.0 nM PMID[20303767]
NPT5634 Individual protein Mycothiol S-conjugate amidase Mycobacterium tuberculosis IC50 = 70000.0 nM PMID[10924160]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT15 Cell line Jurkat Homo sapiens IC50 = 94900.0 nM PMID[17981473]
NPT65 Cell line HepG2 Homo sapiens IC50 > 100000.0 nM PMID[20476748]
NPT397 Cell line NCI-H460 Homo sapiens IC50 > 100000.0 nM PMID[20038624]
NPT83 Cell line MCF7 Homo sapiens IC50 > 100000.0 nM DOI[10.6019/CHEMBL1201861]
NPT395 Cell line SF-268 Homo sapiens IC50 > 100000.0 nM PMID[22304303]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. IC50 = 24.0 ug.mL-1 PMID[14738397]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. IC50 = 24000.0 nM PMID[20303767]
NPT471 Organism Trypanosoma brucei brucei Trypanosoma brucei brucei IC50 = 5900.0 nM PMID[22522694]
NPT2 Others Unspecified n.a. IC50 > 50000.0 nM PMID[9249972]
NPT2 Others Unspecified n.a. Ratio IC50 = 16.1 uM PMID[7400822]

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 NPC294693 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
0.6087 Remote Similarity NPC163055
0.5882 Remote Similarity NPC248454
0.5395 Remote Similarity NPC484607
0.527 Remote Similarity NPC470499

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC294693 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