Natural Product: NPC65591

Natural Product IDNPC65591
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 3',4'-Demethylene-4-Demethyl-Podophyllotoxin
IUPAC Name (3aR,4R,9R,9aR)-4,6,7-trihydroxy-9-(4-hydroxy-3,5-dimethoxyphenyl)-3a,4,9,9a-tetrahydro-3H-benzo[f][2]benzofuran-1-one
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL99342
PubChem CID 468863
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0001392] Lignans, neolignans and related compounds
      • [CHEMONTID:0001510] Lignan lactones

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 SMPCOLOECPREKW-MJQACMKBSA-N
Standard InCHI InChI=1S/C20H20O8/c1-26-14-3-8(4-15(27-2)19(14)24)16-9-5-12(21)13(22)6-10(9)18(23)11-7-28-20(25)17(11)16/h3-6,11,16-18,21-24H,7H2,1-2H3/t11-,16+,17-,18-/m0/s1
SMILES COc1cc(cc(c1O)OC)[C@@H]1c2cc(c(cc2[C@@H]([C@H]2COC(=O)[C@H]12)O)O)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   388.12 Volume:   372.117
?
Van der Waals volume.
Dense:   1.043 LogP:   0.765
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.065
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.422
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   3.0 Rigid Bonds:   22.0
TPSA:   125.68
?
Topological Polar Surface Area.
 H-Bond Acceptor:   8.0
H-Bond Donor:   4.0 Rings:   4.0
Heavy Atoms:   8.0

MedChem Properties

QED Drug-Likeness Score:   0.463 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.838 Fsp3:   0.35
MCE-18:   84.259
?
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:   1 PAINS Alert:   1
Colloidal aggregators:   0.434 Fluc inhibitor:   0.088
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.209
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.069
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.119 Promiscuous compounds:   0.413

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.511 MDCK Permeability:   -4.892
Pgp-inhibitor:   0.0 Pgp-substrate:   0.081
PAMPA:   0.693
?
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):   0.009
20% Bioavailability (F20%):   0.76 30% Bioavailability (F30%):   0.353
50% Bioavailability (F50%):   0.969

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.049 MRP1:   0.98
Plasma Protein Binding (PPB):   88.791% Volume Distribution (VD):   -0.475
Fu: 11.203%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.96
OATP1B3 inhibitor:   0.84 BCRP inhibitor:   0.034
BSEP inhibitor:   0.014

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.028
CYP2C19-inhibitor:   0.052 CYP2C19-substrate:   0.114
CYP2C9-inhibitor:   0.0 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.0 CYP2D6-substrate:   0.247
CYP3A4-inhibitor:   0.146 CYP3A4-substrate:   1.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   1.0
HLM stability:   0.876
?
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):  10.444 Half-life (T1/2):  2.781

ADMET: Toxicity

hERG Blockers:  0.077 hERG Blockers (10um):  0.623
Human Hepatotoxicity (H-HT):  0.837 Drug-induced Liver Injury (DILI):  0.982
AMES Toxicity:  0.832 Rat Oral Acute Toxicity:  0.86
Maximum Recommended Daily Dose:  0.776 Skin Sensitization:  1.0
Carcinogencity:  0.544 Eye Corrosion:  0.001
Eye Irritation:  0.388 Respiratory Toxicity:  0.944
Drug-induced Neurotoxicity:  0.467 Ototoxicity:  0.842
Hematotoxicity:  0.811 Drug-induced Nephrotoxicity:  0.965
Genotoxicity:  0.992 RPMI-8226 Immunitoxicity:  0.482
A549 Cytotoxicity:  0.989 Hek293 Cytotoxicity:  0.662
BCF:   0.662
?
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:   3.419
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.467
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.987
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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
NPO14752 Sinopodophyllum emodi Species Berberidaceae Eukaryota roots and rhizomes n.a. n.a. PMID[21570846]
NPO11163 Methylobacterium organophilum Species Methylobacteriaceae Bacteria n.a. n.a. n.a. PMID[26032177]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. PMID[26359402]
NPO11163 Methylobacterium organophilum Species Methylobacteriaceae Bacteria n.a. n.a. n.a. PMID[3928379]
NPO4464 Senecio mexicanus Species Asteraceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3025 Schefflera capitata Species Araliaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO6893 Dimorphotheca sinuata Species Asteraceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO14752 Sinopodophyllum emodi Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TM-MC]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO4464 Senecio mexicanus Species Asteraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO11417 Gesneria cardinalis Species Crambidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO11163 Methylobacterium organophilum Species Methylobacteriaceae Bacteria n.a. n.a. n.a. Database[UNPD]
NPO3025 Schefflera capitata Species Araliaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO14752 Sinopodophyllum emodi Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO6893 Dimorphotheca sinuata Species Asteraceae 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

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT759 Cell line H9 Homo sapiens IC50 = 1850.0 nM DOI[10.1016/S0960-894X(97)10108-1]
NPT165 Cell line HeLa Homo sapiens IC50 = 79600.0 nM PMID[21570846]
NPT91 Cell line KB Homo sapiens IC50 > 100000.0 nM PMID[21570846]

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 NPC65591 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
0.8214 Intermediate Similarity NPC178574
0.7097 Intermediate Similarity NPC91634
0.7097 Intermediate Similarity NPC150943
0.7097 Intermediate Similarity NPC268718
0.5606 Remote Similarity NPC237946
0.5606 Remote Similarity NPC32373
0.5286 Remote Similarity NPC119910

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC65591 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
0.5606 Remote Similarity NPD4965 Approved
0.5606 Remote Similarity NPD4966 Phase 4
0.5606 Remote Similarity NPD4967 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