Natural Product: NPC311737

Natural Product IDNPC311737
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Cyclo(-Trp-Tyr)
IUPAC Name (3S,6S)-3,6-bis[(4-hydroxyphenyl)methyl]piperazine-2,5-dione
Synonyms Cyclo(-Trp-Tyr)
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL189558
PubChem CID 11267350
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 NGPCLOGFGKJCBP-HOTGVXAUSA-N
Standard InCHI InChI=1S/C18H18N2O4/c21-13-5-1-11(2-6-13)9-15-17(23)20-16(18(24)19-15)10-12-3-7-14(22)8-4-12/h1-8,15-16,21-22H,9-10H2,(H,19,24)(H,20,23)/t15-,16-/m0/s1
SMILES OC1=N[C@@H](Cc2ccc(cc2)O)C(=N[C@H]1Cc1ccc(cc1)O)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   326.13 Volume:   330.278
?
Van der Waals volume.
Dense:   0.987 LogP:   0.966
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.501
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.821
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   18.0
TPSA:   105.64
?
Topological Polar Surface Area.
 H-Bond Acceptor:   6.0
H-Bond Donor:   4.0 Rings:   3.0
Heavy Atoms:   6.0

MedChem Properties

QED Drug-Likeness Score:   0.693 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.442 Fsp3:   0.222
MCE-18:   54.091
?
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:   0.54 Fluc inhibitor:   0.335
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.032
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.381
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.15 Promiscuous compounds:   0.252

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.136 MDCK Permeability:   -4.773
Pgp-inhibitor:   0.017 Pgp-substrate:   0.834
PAMPA:   0.88
?
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):   0.03
20% Bioavailability (F20%):   0.977 30% Bioavailability (F30%):   0.978
50% Bioavailability (F50%):   1.0

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.005 MRP1:   0.339
Plasma Protein Binding (PPB):   81.52% Volume Distribution (VD):   -0.11
Fu: 19.066%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.987
OATP1B3 inhibitor:   0.984 BCRP inhibitor:   0.193
BSEP inhibitor:   0.809

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.001
CYP2C19-inhibitor:   0.729 CYP2C19-substrate:   0.962
CYP2C9-inhibitor:   0.813 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.646 CYP2D6-substrate:   0.999
CYP3A4-inhibitor:   1.0 CYP3A4-substrate:   0.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.007
HLM stability:   0.943
?
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):  10.075 Half-life (T1/2):  1.492

ADMET: Toxicity

hERG Blockers:  0.139 hERG Blockers (10um):  0.132
Human Hepatotoxicity (H-HT):  1.0 Drug-induced Liver Injury (DILI):  0.973
AMES Toxicity:  0.081 Rat Oral Acute Toxicity:  0.707
Maximum Recommended Daily Dose:  0.909 Skin Sensitization:  1.0
Carcinogencity:  0.015 Eye Corrosion:  0.0
Eye Irritation:  0.806 Respiratory Toxicity:  0.731
Drug-induced Neurotoxicity:  0.307 Ototoxicity:  0.66
Hematotoxicity:  0.335 Drug-induced Nephrotoxicity:  0.916
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.005
A549 Cytotoxicity:  0.0 Hek293 Cytotoxicity:  0.389
BCF:   1.152
?
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:   3.622
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.377
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.947
?
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
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. mycelium n.a. PMID[10423860]
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. n.a. n.a. PMID[15863936]
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. mycelium n.a. PMID[21848266]
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. n.a. n.a. PMID[21848266]
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO30270 Cordyceps sinensis Species Cordycipitaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]

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
NPT3579 Individual protein Calpain 1 Homo sapiens Inhibition = 0.0 % PMID[15896956]
NPT26232 Single protein Cytochrome P450 Mycobacterium tuberculosis Kd = 30000.0 nM PMID[31618032]
NPT26232 Single protein Cytochrome P450 Mycobacterium tuberculosis Activity = 52.0 % PMID[31618032]
NPT26232 Single protein Cytochrome P450 Mycobacterium tuberculosis Activity = 2.7 % PMID[31618032]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT878 Organism Streptococcus mutans Streptococcus mutans MIC = 96.0 ug.mL-1 PMID[30528685]
NPT878 Organism Streptococcus mutans Streptococcus mutans MBC > 192.0 ug ml-1 PMID[30528685]
NPT28438 Unchecked Unchecked n.a. Kd = 17200.0 nM PMID[35065413]
NPT28438 Unchecked Unchecked n.a. OD = 395.0 nm PMID[36426236]
NPT28438 Unchecked Unchecked n.a. Kd = 12300.0 nM PMID[36426236]
NPT564 Organism Listeria monocytogenes Listeria monocytogenes MIC > 192.0 ug.mL-1 PMID[30528685]
NPT20 Organism Candida albicans Candida albicans Activity = 20.0 % PMID[30528685]
NPT19 Organism Escherichia coli Escherichia coli MIC > 192.0 ug.mL-1 PMID[30528685]
NPT18 Organism Pseudomonas aeruginosa Pseudomonas aeruginosa MIC > 192.0 ug.mL-1 PMID[30528685]
NPT16 Organism Staphylococcus aureus Staphylococcus aureus MIC > 192.0 ug.mL-1 PMID[30528685]

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 NPC311737 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
1.0 High Similarity NPC38458
0.8824 High Similarity NPC82963
0.75 Intermediate Similarity NPC118202
0.6667 Remote Similarity NPC479749
0.6471 Remote Similarity NPC311242
0.625 Remote Similarity NPC486124
0.6122 Remote Similarity NPC479753
0.5918 Remote Similarity NPC479751
0.5769 Remote Similarity NPC192615
0.5686 Remote Similarity NPC317254
0.5641 Remote Similarity NPC621
0.55 Remote Similarity NPC303045
0.5472 Remote Similarity NPC479750
0.5143 Remote Similarity NPC107619
0.5116 Remote Similarity NPC25565
0.5116 Remote Similarity NPC161972
0.5116 Remote Similarity NPC475439

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC311737 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
0.5179 Remote Similarity NPD5729 Clinical (unspecified phase)
0.5085 Remote Similarity NPD7451 Phase 2

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