Natural Product: NPC474561

Natural Product IDNPC474561
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Cyclo-(D-Ile-L-Trp)
IUPAC Name (3R,6S)-3-[(2S)-butan-2-yl]-6-(1H-indol-3-ylmethyl)piperazine-2,5-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL472229
PubChem CID 44575417
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 PGCNHGBQEYFZEX-NZVBXONLSA-N
Standard InCHI InChI=1S/C17H21N3O2/c1-3-10(2)15-17(22)19-14(16(21)20-15)8-11-9-18-13-7-5-4-6-12(11)13/h4-7,9-10,14-15,18H,3,8H2,1-2H3,(H,19,22)(H,20,21)/t10-,14-,15+/m0/s1
SMILES CCC(C)C1C(=O)NC(C(=O)N1)CC2=CNC3=CC=CC=C32

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   299.16 Volume:   311.671
?
Van der Waals volume.
Dense:   0.96 LogP:   2.141
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.378
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.654
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   18.0
TPSA:   73.99
?
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:   0.804 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.267 Fsp3:   0.412
MCE-18:   53.833
?
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:   0.494 Fluc inhibitor:   0.342
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.131
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.577
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.004 Promiscuous compounds:   0.004

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.143 MDCK Permeability:   -4.786
Pgp-inhibitor:   0.696 Pgp-substrate:   0.14
PAMPA:   0.182
?
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):   0.419
20% Bioavailability (F20%):   0.465 30% Bioavailability (F30%):   0.904
50% Bioavailability (F50%):   0.97

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.17 MRP1:   0.675
Plasma Protein Binding (PPB):   82.479% Volume Distribution (VD):   -0.292
Fu: 17.079%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.241
OATP1B3 inhibitor:   0.923 BCRP inhibitor:   0.174
BSEP inhibitor:   0.992

ADMET: Metabolism

CYP1A2-inhibitor:   0.001 CYP1A2-substrate:   0.298
CYP2C19-inhibitor:   0.699 CYP2C19-substrate:   0.001
CYP2C9-inhibitor:   0.628 CYP2C9-substrate:   0.001
CYP2D6-inhibitor:   0.641 CYP2D6-substrate:   0.853
CYP3A4-inhibitor:   0.011 CYP3A4-substrate:   0.012
CYP2B6-substrate:   0.215 CYP2C8-inhibitor:   0.104
HLM stability:   0.831
?
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):  3.569 Half-life (T1/2):  1.198

ADMET: Toxicity

hERG Blockers:  0.038 hERG Blockers (10um):  0.409
Human Hepatotoxicity (H-HT):  0.716 Drug-induced Liver Injury (DILI):  0.542
AMES Toxicity:  0.164 Rat Oral Acute Toxicity:  0.487
Maximum Recommended Daily Dose:  0.571 Skin Sensitization:  0.002
Carcinogencity:  0.293 Eye Corrosion:  0.0
Eye Irritation:  0.011 Respiratory Toxicity:  0.302
Drug-induced Neurotoxicity:  0.983 Ototoxicity:  0.719
Hematotoxicity:  0.207 Drug-induced Nephrotoxicity:  0.151
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.117
A549 Cytotoxicity:  0.037 Hek293 Cytotoxicity:  0.26
BCF:   0.529
?
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:   3.244
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.573
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.03
?
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
NPO33398 penicillium brevi-compactum Species Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[15730251]

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
NPT364 Organism Lactuca sativa Lactuca sativa Activity = 167.0 % PMID[22037378]

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 NPC474561 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
0.7963 Intermediate Similarity NPC602670
0.746 Intermediate Similarity NPC600670
0.7119 Intermediate Similarity NPC606619
0.7119 Intermediate Similarity NPC610347
0.7083 Intermediate Similarity NPC601763
0.6986 Remote Similarity NPC610080
0.6857 Remote Similarity NPC601302
0.6761 Remote Similarity NPC605408
0.662 Remote Similarity NPC610128
0.6508 Remote Similarity NPC603509
0.6508 Remote Similarity NPC605537
0.6351 Remote Similarity NPC600013
0.6351 Remote Similarity NPC601387
0.6351 Remote Similarity NPC605600
0.6133 Remote Similarity NPC604088
0.5946 Remote Similarity NPC604280
0.5814 Remote Similarity NPC600238
0.5802 Remote Similarity NPC326845
0.5802 Remote Similarity NPC603279
0.5584 Remote Similarity NPC602956
0.5529 Remote Similarity NPC473640
0.5476 Remote Similarity NPC600277
0.5362 Remote Similarity NPC602245
0.5362 Remote Similarity NPC606412
0.5323 Remote Similarity NPC200214
0.5323 Remote Similarity NPC608269
0.5303 Remote Similarity NPC605381
0.5169 Remote Similarity NPC602438
0.5057 Remote Similarity NPC603138

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC474561 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