Natural Product: NPC150943

Natural Product IDNPC150943
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 4'-Demethylpodophyllotoxin
IUPAC Name (5R,5aR,8aR,9R)-5-hydroxy-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
Synonyms 4'-Demethyl-Podophyllotoxin; 4'-Demethylpodophyllotoxin; 4-Demethyl-Podophyllotoxin
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL28941
PubChem CID 122667
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0001392] Lignans, neolignans and related compounds
      • [CHEMONTID:0001510] Lignan lactones
        • [CHEMONTID:0000047] Podophyllotoxins

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 YVCVYCSAAZQOJI-BTINSWFASA-N
Standard InCHI InChI=1S/C21H20O8/c1-25-15-3-9(4-16(26-2)20(15)23)17-10-5-13-14(29-8-28-13)6-11(10)19(22)12-7-27-21(24)18(12)17/h3-6,12,17-19,22-23H,7-8H2,1-2H3/t12-,17+,18-,19-/m0/s1
SMILES COc1cc(cc(c1O)OC)[C@@H]1c2cc3c(cc2[C@@H]([C@H]2COC(=O)[C@H]12)O)OCO3

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   400.12 Volume:   380.856
?
Van der Waals volume.
Dense:   1.051 LogP:   1.471
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.753
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.815
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   3.0 Rigid Bonds:   26.0
TPSA:   103.68
?
Topological Polar Surface Area.
 H-Bond Acceptor:   8.0
H-Bond Donor:   2.0 Rings:   5.0
Heavy Atoms:   8.0

MedChem Properties

QED Drug-Likeness Score:   0.755 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.814 Fsp3:   0.381
MCE-18:   95.586
?
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:   Rejected BMS Rule:   0
Chelating Alert:   1 PAINS Alert:   0
Colloidal aggregators:   0.515 Fluc inhibitor:   0.101
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.193
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.013
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.068 Promiscuous compounds:   0.763

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.357 MDCK Permeability:   -4.888
Pgp-inhibitor:   0.068 Pgp-substrate:   0.037
PAMPA:   0.159
?
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):   0.0
20% Bioavailability (F20%):   0.013 30% Bioavailability (F30%):   0.0
50% Bioavailability (F50%):   0.148

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.828 MRP1:   0.974
Plasma Protein Binding (PPB):   97.768% Volume Distribution (VD):   -0.391
Fu: 2.403%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.857
OATP1B3 inhibitor:   0.382 BCRP inhibitor:   0.005
BSEP inhibitor:   0.958

ADMET: Metabolism

CYP1A2-inhibitor:   0.007 CYP1A2-substrate:   0.956
CYP2C19-inhibitor:   0.82 CYP2C19-substrate:   0.622
CYP2C9-inhibitor:   0.001 CYP2C9-substrate:   0.975
CYP2D6-inhibitor:   0.0 CYP2D6-substrate:   0.987
CYP3A4-inhibitor:   0.702 CYP3A4-substrate:   1.0
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.694
HLM stability:   0.754
?
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):  5.34 Half-life (T1/2):  2.708

ADMET: Toxicity

hERG Blockers:  0.118 hERG Blockers (10um):  0.568
Human Hepatotoxicity (H-HT):  0.837 Drug-induced Liver Injury (DILI):  0.99
AMES Toxicity:  0.842 Rat Oral Acute Toxicity:  0.883
Maximum Recommended Daily Dose:  0.803 Skin Sensitization:  0.995
Carcinogencity:  0.844 Eye Corrosion:  0.0
Eye Irritation:  0.225 Respiratory Toxicity:  0.961
Drug-induced Neurotoxicity:  0.829 Ototoxicity:  0.751
Hematotoxicity:  0.928 Drug-induced Nephrotoxicity:  0.987
Genotoxicity:  0.993 RPMI-8226 Immunitoxicity:  0.695
A549 Cytotoxicity:  0.958 Hek293 Cytotoxicity:  0.74
BCF:   0.655
?
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:   3.41
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.703
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.989
?
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
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota Roots Panan, Zhejiang Province, China 2004-MAY PMID[17256902]
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota n.a. root n.a. PMID[17256902]
NPO14752 Sinopodophyllum emodi Species Berberidaceae Eukaryota roots and rhizomes n.a. n.a. PMID[21570846]
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota n.a. n.a. n.a. PMID[25712646]
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]
NPO1362 Swertia paniculata Species Gentianaceae Eukaryota n.a. n.a. n.a. Database[Article]
NPO6738 Cladonia incrassata Species Cladoniaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO14752 Sinopodophyllum emodi 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]
NPO26868 Diphylleia sinensis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3158 Linum album Species Linaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3025 Schefflera capitata Species Araliaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO4464 Senecio mexicanus Species Asteraceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO1362 Swertia paniculata Species Gentianaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3158 Linum album Species Linaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO26868 Diphylleia sinensis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO26868 Diphylleia sinensis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO3158 Linum album Species Linaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO3158 Linum album Species Linaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO30053 Podophyllum emodll Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO26868 Diphylleia sinensis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[TM-MC]
NPO26868 Diphylleia sinensis 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]
NPO6893 Dimorphotheca sinuata Species Asteraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO14752 Sinopodophyllum emodi Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO3025 Schefflera capitata Species Araliaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO11163 Methylobacterium organophilum Species Methylobacteriaceae Bacteria n.a. n.a. n.a. Database[UNPD]
NPO11417 Gesneria cardinalis Species Crambidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO4534 Croton nitens Species Euphorbiaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO10903 Sinopodophyllum hexandrum Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO17807 Dysosma versipellis Species Berberidaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO6738 Cladonia incrassata Species Cladoniaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO3158 Linum album Species Linaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO1362 Swertia paniculata Species Gentianaceae 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
NPT12 Individual protein Human immunodeficiency virus type 1 integrase Human immunodeficiency virus 1 Inhibition < 5.0 % PMID[8568830]
NPT1044 Individual protein DNA topoisomerase II alpha Homo sapiens ID50 > 100.0 uM PMID[1331331]
NPT1044 Individual protein DNA topoisomerase II alpha Homo sapiens Activity = 1.1 % PMID[1331331]
NPT1044 Individual protein DNA topoisomerase II alpha Homo sapiens Inhibition = 25.0 % PMID[2550587]
NPT1044 Individual protein DNA topoisomerase II alpha Homo sapiens Inhibition = 3.3 % PMID[2550587]
NPT320 Protein family DNA topoisomerase II Homo sapiens Protein-DNA complex formation = 3.3 % PMID[8691468]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT3950 Cell line GLC4 cell line n.a. IC50 = 30.0 nM PMID[7783142]
NPT3950 Cell line GLC4 cell line n.a. IC50 = 3100.0 nM PMID[7783142]
NPT306 Cell line PC-3 Homo sapiens IC50 = 82.0 nM PMID[17256902]
NPT858 Cell line LNCaP Homo sapiens IC50 = 56.0 nM PMID[17256902]
NPT91 Cell line KB Homo sapiens ED50 = 0.045 ug ml-1 PMID[2550587]
NPT168 Cell line P388 Mus musculus T/C = 144.0 % DOI[10.1021/np50004a005]
NPT165 Cell line HeLa Homo sapiens IC50 = 80.0 nM PMID[21570846]
NPT91 Cell line KB Homo sapiens IC50 = 64.0 nM PMID[21570846]
NPT190 Organism Human herpesvirus 1 Human herpesvirus 1 Activity = 500.0 nM PMID[9834179]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity > 125.0 uM PMID[9834179]
NPT190 Organism Human herpesvirus 1 Human herpesvirus 1 IC50 = 100.0 nM PMID[9834179]
NPT195 Organism Vesicular stomatitis virus Vesicular stomatitis virus IC50 = 250.0 nM PMID[9834179]

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 NPC150943 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 NPC91634
1.0 High Similarity NPC268718
0.8136 Intermediate Similarity NPC237946
0.8136 Intermediate Similarity NPC32373
0.7619 Intermediate Similarity NPC119910
0.7097 Intermediate Similarity NPC65591
0.6515 Remote Similarity NPC30009
0.6515 Remote Similarity NPC103197
0.6269 Remote Similarity NPC207584
0.6269 Remote Similarity NPC19947
0.6061 Remote Similarity NPC178574
0.6 Remote Similarity NPC288149
0.5915 Remote Similarity NPC163527
0.5373 Remote Similarity NPC477695
0.5294 Remote Similarity NPC239890
0.5294 Remote Similarity NPC209411
0.5238 Remote Similarity NPC116759
0.5238 Remote Similarity NPC14294
0.5211 Remote Similarity NPC477699
0.5114 Remote Similarity NPC185498
0.5072 Remote Similarity NPC477700

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC150943 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
0.8136 Intermediate Similarity NPD4965 Approved
0.8136 Intermediate Similarity NPD4966 Phase 4
0.8136 Intermediate Similarity NPD4967 Phase 2
0.6234 Remote Similarity NPD37 Approved
0.5733 Remote Similarity NPD6234 Discontinued
0.5443 Remote Similarity NPD7090 Clinical (unspecified phase)
0.5114 Remote Similarity NPD7228 Phase 4
0.5059 Remote Similarity NPD6723 Discontinued

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