Natural Product: NPC219966

Natural Product IDNPC219966
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 (+)-Miliusane Xviii
IUPAC Name methyl 2-[(1R,5S)-5-hydroxy-1-[(1R,2E)-1-hydroxy-3,7-dimethylocta-2,6-dienyl]-2-oxocyclohex-3-en-1-yl]acetate
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL2448545
PubChem CID 44406789
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000012] Lipids and lipid-like molecules
      • [CHEMONTID:0000259] Prenol lipids
        • [CHEMONTID:0001549] Monoterpenoids
          • [CHEMONTID:0001563] Monocyclic monoterpenoids

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 LRHXPNHCPURRDF-OROLVADBSA-N
Standard InCHI InChI=1S/C19H28O5/c1-13(2)6-5-7-14(3)10-17(22)19(12-18(23)24-4)11-15(20)8-9-16(19)21/h6,8-10,15,17,20,22H,5,7,11-12H2,1-4H3/b14-10+/t15-,17-,19+/m1/s1
SMILES CC(=CCC/C(=C/[C@H]([C@@]1(C[C@@H](C=CC1=O)O)CC(=O)OC)O)/C)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   336.19 Volume:   359.393
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Van der Waals volume.
Dense:   0.935 LogP:   2.174
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.186
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.34
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   8.0 Rigid Bonds:   10.0
TPSA:   83.83
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   2.0 Rings:   1.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.551 GASA:   1.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.417 Fsp3:   0.579
MCE-18:   26.4
?
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:   0.451 Fluc inhibitor:   0.033
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.14
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.12
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.656 Promiscuous compounds:   0.246

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.596 MDCK Permeability:   -4.696
Pgp-inhibitor:   0.475 Pgp-substrate:   0.016
PAMPA:   0.326
?
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):   0.078
20% Bioavailability (F20%):   0.085 30% Bioavailability (F30%):   0.317
50% Bioavailability (F50%):   0.967

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.216 MRP1:   0.686
Plasma Protein Binding (PPB):   66.929% Volume Distribution (VD):   -0.32
Fu: 30.461%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.999
OATP1B3 inhibitor:   0.997 BCRP inhibitor:   0.021
BSEP inhibitor:   0.949

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.09
CYP2C19-inhibitor:   0.012 CYP2C19-substrate:   0.006
CYP2C9-inhibitor:   0.002 CYP2C9-substrate:   0.004
CYP2D6-inhibitor:   0.008 CYP2D6-substrate:   0.786
CYP3A4-inhibitor:   0.0 CYP3A4-substrate:   0.04
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.237
HLM stability:   0.994
?
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):  9.727 Half-life (T1/2):  1.375

ADMET: Toxicity

hERG Blockers:  0.029 hERG Blockers (10um):  0.297
Human Hepatotoxicity (H-HT):  0.711 Drug-induced Liver Injury (DILI):  0.188
AMES Toxicity:  0.514 Rat Oral Acute Toxicity:  0.789
Maximum Recommended Daily Dose:  0.628 Skin Sensitization:  0.989
Carcinogencity:  0.754 Eye Corrosion:  0.045
Eye Irritation:  0.85 Respiratory Toxicity:  0.906
Drug-induced Neurotoxicity:  0.789 Ototoxicity:  0.463
Hematotoxicity:  0.53 Drug-induced Nephrotoxicity:  0.891
Genotoxicity:  0.475 RPMI-8226 Immunitoxicity:  0.114
A549 Cytotoxicity:  0.642 Hek293 Cytotoxicity:  0.099
BCF:   1.281
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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:   4.016
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.614
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.935
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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
NPO22093 Miliusa sinensis Species Annonaceae Eukaryota dried leaves, twigs, and flowers Vietnam n.a. PMID[16420055]
NPO22093 Miliusa sinensis Species Annonaceae 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
NPT91 Cell line KB Homo sapiens IC50 = 3070.0 nM PMID[15620248]
NPT1034 Cell line Lu1 Homo sapiens IC50 = 1820.0 nM PMID[20576577]
NPT1851 Cell line Col2 Homo sapiens IC50 = 2260.0 nM PMID[25237727]
NPT858 Cell line LNCaP Homo sapiens IC50 = 2410.0 nM PMID[15711537]
NPT83 Cell line MCF7 Homo sapiens IC50 = 3010.0 nM PMID[22260257]
NPT116 Cell line HL-60 Homo sapiens IC50 = 630.0 nM PMID[19223615]

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 NPC219966 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
0.5636 Remote Similarity NPC87306
0.5179 Remote Similarity NPC599954

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC219966 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