Natural Product: NPC299090

Natural Product IDNPC299090
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Cimicifugic Acid N
IUPAC Name (2R,3S)-2-[(3,4-dihydroxyphenyl)methyl]-3-[(Z)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]oxy-2-hydroxybutanedioic acid
Synonyms Cimicifugic Acid N
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL1094303
PubChem CID 46210734
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000261] Phenylpropanoids and polyketides
      • [CHEMONTID:0000476] Cinnamic acids and derivatives
        • [CHEMONTID:0001391] Hydroxycinnamic acids and derivatives
          • [CHEMONTID:0000059] Coumaric 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 YMPYAGUNPNITIL-SAEXZTQASA-N
Standard InCHI InChI=1S/C22H22O11/c1-31-16-7-4-12(10-17(16)32-2)5-8-18(25)33-19(20(26)27)22(30,21(28)29)11-13-3-6-14(23)15(24)9-13/h3-10,19,23-24,30H,11H2,1-2H3,(H,26,27)(H,28,29)/b8-5-/t19-,22-/m1/s1
SMILES COc1cc(/C=CC(=O)O[C@@H]([C@@](C(=O)O)(Cc2ccc(c(c2)O)O)O)C(=O)O)ccc1OC

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   462.12 Volume:   442.283
?
Van der Waals volume.
Dense:   1.045 LogP:   1.661
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.912
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.907
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   11.0 Rigid Bonds:   16.0
TPSA:   180.05
?
Topological Polar Surface Area.
 H-Bond Acceptor:   11.0
H-Bond Donor:   5.0 Rings:   2.0
Heavy Atoms:   11.0

MedChem Properties

QED Drug-Likeness Score:   0.194 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.464 Fsp3:   0.227
MCE-18:   38.0
?
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:   Rejected BMS Rule:   0
Chelating Alert:   1 PAINS Alert:   1
Colloidal aggregators:   0.457 Fluc inhibitor:   0.961
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.033
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.514
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.305 Promiscuous compounds:   0.182

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -6.087 MDCK Permeability:   -5.242
Pgp-inhibitor:   0.0 Pgp-substrate:   0.001
PAMPA:   0.968
?
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):   0.26
20% Bioavailability (F20%):   0.769 30% Bioavailability (F30%):   0.872
50% Bioavailability (F50%):   0.997

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.0 MRP1:   0.38
Plasma Protein Binding (PPB):   81.865% Volume Distribution (VD):   -0.562
Fu: 16.079%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.999
OATP1B3 inhibitor:   1.0 BCRP inhibitor:   0.014
BSEP inhibitor:   0.475

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.0
CYP2C19-inhibitor:   0.0 CYP2C19-substrate:   0.001
CYP2C9-inhibitor:   0.91 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.006 CYP2D6-substrate:   0.0
CYP3A4-inhibitor:   0.0 CYP3A4-substrate:   0.052
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.951
HLM stability:   0.01
?
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):  5.848 Half-life (T1/2):  2.564

ADMET: Toxicity

hERG Blockers:  0.028 hERG Blockers (10um):  0.038
Human Hepatotoxicity (H-HT):  0.579 Drug-induced Liver Injury (DILI):  0.659
AMES Toxicity:  0.291 Rat Oral Acute Toxicity:  0.11
Maximum Recommended Daily Dose:  0.321 Skin Sensitization:  1.0
Carcinogencity:  0.051 Eye Corrosion:  0.019
Eye Irritation:  0.827 Respiratory Toxicity:  0.213
Drug-induced Neurotoxicity:  0.026 Ototoxicity:  0.864
Hematotoxicity:  0.051 Drug-induced Nephrotoxicity:  0.766
Genotoxicity:  0.91 RPMI-8226 Immunitoxicity:  0.014
A549 Cytotoxicity:  0.21 Hek293 Cytotoxicity:  0.042
BCF:   0.599
?
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:   3.503
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.7
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.316
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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
NPO30451 Cimicifuga simplex n.a. n.a. n.a. n.a. n.a. n.a. PMID[17503850]
NPO33345 cimicifuga japonica Species Ranunculaceae Eukaryota aerial parts n.a. n.a. PMID[20184336]
NPO30451 Cimicifuga simplex n.a. n.a. n.a. aerial parts n.a. n.a. PMID[20184336]
NPO30451 Cimicifuga simplex n.a. n.a. n.a. n.a. n.a. n.a. Database[COCONUT]
NPO30451 Cimicifuga simplex n.a. n.a. n.a. n.a. n.a. n.a. Database[HerDing]
NPO30451 Cimicifuga simplex n.a. n.a. n.a. 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
NPT42 Individual protein Hyaluronidase-1 Homo sapiens IC50 = 120000.0 nM PMID[18183025]

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





 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 NPC299090 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 NPC143892
0.8571 High Similarity NPC304956
0.8308 Intermediate Similarity NPC283081
0.8281 Intermediate Similarity NPC221383
0.8154 Intermediate Similarity NPC246566
0.7742 Intermediate Similarity NPC179505
0.75 Intermediate Similarity NPC156709
0.7468 Intermediate Similarity NPC44507
0.7206 Intermediate Similarity NPC258671
0.697 Remote Similarity NPC279676
0.6957 Remote Similarity NPC95498
0.6957 Remote Similarity NPC53884
0.6716 Remote Similarity NPC67349
0.6615 Remote Similarity NPC108553
0.6506 Remote Similarity NPC223335
0.6506 Remote Similarity NPC40920
0.5694 Remote Similarity NPC289690
0.5679 Remote Similarity NPC300329
0.5672 Remote Similarity NPC18074
0.5672 Remote Similarity NPC5419
0.5672 Remote Similarity NPC25581
0.5672 Remote Similarity NPC61
0.5507 Remote Similarity NPC198388
0.5286 Remote Similarity NPC229264
0.519 Remote Similarity NPC160378
0.5156 Remote Similarity NPC217052
0.5156 Remote Similarity NPC329344
0.5156 Remote Similarity NPC237506
0.5156 Remote Similarity NPC32626
0.5147 Remote Similarity NPC251407
0.5147 Remote Similarity NPC168653

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC299090 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