Natural Product: NPC326860

Natural Product IDNPC326860
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Thyroxine
IUPAC Name 2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL42115
PubChem CID 853
25201456
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
              • [CHEMONTID:0004321] Phenylalanine 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 XUIIKFGFIJCVMT-UHFFFAOYSA-N
Standard InCHI InChI=1S/C15H11I4NO4/c16-8-4-7(5-9(17)13(8)21)24-14-10(18)1-6(2-11(14)19)3-12(20)15(22)23/h1-2,4-5,12,21H,3,20H2,(H,22,23)
SMILES OC(=O)C(Cc1cc(I)c(c(c1)I)Oc1cc(I)c(c(c1)I)O)N

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   776.69 Volume:   379.693
?
Van der Waals volume.
Dense:   2.046 LogP:   2.561
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.721
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.573
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   5.0 Rigid Bonds:   13.0
TPSA:   92.78
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   4.0 Rings:   2.0
Heavy Atoms:   9.0

MedChem Properties

QED Drug-Likeness Score:   0.388 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.366 Fsp3:   0.133
MCE-18:   32.0
?
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:   Accepted
Golden Triangle Rule:   Accepted BMS Rule:   1
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.735 Fluc inhibitor:   0.019
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.002
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.001
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.167 Promiscuous compounds:   0.743

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.027 MDCK Permeability:   -4.727
Pgp-inhibitor:   0.0 Pgp-substrate:   0.0
PAMPA:   1.0
?
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):   0.68
20% Bioavailability (F20%):   0.0 30% Bioavailability (F30%):   0.0
50% Bioavailability (F50%):   0.028

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.0 MRP1:   0.994
Plasma Protein Binding (PPB):   97.83% Volume Distribution (VD):   0.319
Fu: 1.661%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.469
OATP1B3 inhibitor:   0.256 BCRP inhibitor:   0.073
BSEP inhibitor:   0.987

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.0
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   1.0
CYP2C9-inhibitor:   1.0 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   1.0 CYP2D6-substrate:   0.0
CYP3A4-inhibitor:   1.0 CYP3A4-substrate:   1.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   1.0
HLM stability:   0.999
?
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):  2.606 Half-life (T1/2):  0.951

ADMET: Toxicity

hERG Blockers:  0.449 hERG Blockers (10um):  0.543
Human Hepatotoxicity (H-HT):  0.538 Drug-induced Liver Injury (DILI):  0.002
AMES Toxicity:  0.094 Rat Oral Acute Toxicity:  0.895
Maximum Recommended Daily Dose:  0.958 Skin Sensitization:  0.14
Carcinogencity:  0.476 Eye Corrosion:  0.0
Eye Irritation:  0.031 Respiratory Toxicity:  0.96
Drug-induced Neurotoxicity:  0.017 Ototoxicity:  0.788
Hematotoxicity:  0.121 Drug-induced Nephrotoxicity:  0.156
Genotoxicity:  0.995 RPMI-8226 Immunitoxicity:  0.105
A549 Cytotoxicity:  0.507 Hek293 Cytotoxicity:  0.175
BCF:   1.838
?
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:   5.515
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   6.248
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   5.871
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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
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. n.a. PMID[24211545]
NPO12323 Bos taurus Species Bovidae Eukaryota Urine n.a. n.a. PMID[6330305]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. n.a. PMID[932730]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. Database[FooDB]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. Database[FooDB]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO12323 Bos taurus Species Bovidae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO12323 Bos taurus Species Bovidae 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
NPT149 Individual protein Endoplasmic reticulum-associated amyloid beta-peptide-binding protein Homo sapiens Potency = 10000.0 nM PubChem BioAssay data set
NPT109 Individual protein Cytochrome P450 3A4 Homo sapiens Potency = 31622.8 nM PubChem BioAssay data set
NPT198 Individual protein Vitamin D receptor Homo sapiens Potency n.a. 50118.7 nM PubChem BioAssay data set
NPT199 Individual protein DNA polymerase kappa Homo sapiens Potency n.a. 35481.3 nM PubChem BioAssay data set
NPT1250 Individual protein Macrophage migration inhibitory factor Homo sapiens IC50 = 15800.0 nM PMID[29812929]
NPT77 Individual protein Transthyretin Homo sapiens Concentration = 0.000000016 M PMID[3009810]
NPT77 Individual protein Transthyretin Homo sapiens Binding affinity = 63.0 n.a. PMID[3009810]
NPT94 Individual protein Aldehyde dehydrogenase 1A1 Homo sapiens Potency = 15848.9 nM PubChem BioAssay data set
NPT444 Individual protein Ubiquitin carboxyl-terminal hydrolase 1 Homo sapiens Potency n.a. 56234.1 nM PubChem BioAssay data set
NPT51 Individual protein Microtubule-associated protein tau Homo sapiens Potency = 22387.2 nM PubChem BioAssay data set
NPT792 Individual protein Arachidonate 15-lipoxygenase Homo sapiens Potency = 12589.3 nM PubChem BioAssay data set
NPT5122 Individual protein Thyroxine-binding globulin Homo sapiens RBA = 100.0 % PMID[195056]
NPT5122 Individual protein Thyroxine-binding globulin Homo sapiens log(%) = 2.0 n.a. PMID[195056]
NPT197 Protein-protein interaction Menin/Histone-lysine N-methyltransferase MLL Homo sapiens Potency = 10000.0 nM PubChem BioAssay data set
NPT45 Individual protein Ubiquitin carboxyl-terminal hydrolase 2 Homo sapiens Potency = 25118.9 nM PubChem BioAssay data set
NPT443 Individual protein Histone acetyltransferase GCN5 Homo sapiens Potency n.a. 39810.7 nM PubChem BioAssay data set

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference

In vivo activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT29 Organism Rattus norvegicus Rattus norvegicus Activity = 18.1 % PMID[195056]
NPT29 Organism Rattus norvegicus Rattus norvegicus log(%) = 1.258 n.a. PMID[195056]





 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 NPC326860 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 NPC197239
0.78 Intermediate Similarity NPC282087
0.78 Intermediate Similarity NPC317741
0.7551 Intermediate Similarity NPC318984
0.7451 Intermediate Similarity NPC328137
0.7451 Intermediate Similarity NPC259800
0.6444 Remote Similarity NPC142638
0.6444 Remote Similarity NPC317784
0.5965 Remote Similarity NPC241086
0.5965 Remote Similarity NPC318028
0.5098 Remote Similarity NPC48909
0.5098 Remote Similarity NPC239697

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC326860 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
1.0 High Similarity NPD1522 Phase 4
1.0 High Similarity NPD1523 Phase 4
0.78 Intermediate Similarity NPD1537 Phase 4
0.78 Intermediate Similarity NPD1538 Phase 1
0.75 Intermediate Similarity NPD1520 Approved
0.75 Intermediate Similarity NPD1521 Approved
0.6863 Remote Similarity NPD1536 Approved
0.6667 Remote Similarity NPD1519 Approved
0.6444 Remote Similarity NPD9718 Pre-clinical
0.5455 Remote Similarity NPD1535 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