Natural Product: NPC279676

Natural Product IDNPC279676
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Cimicifugic Acid D
IUPAC Name (2R,3S)-3-[(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxy-2-hydroxy-2-[(4-hydroxyphenyl)methyl]butanedioic acid
Synonyms Cimicifugic Acid D
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL1095596
PubChem CID 11742743
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 MTGTYFYLZVUKQG-ZUVWSUMTSA-N
Standard InCHI InChI=1S/C20H18O10/c21-13-5-1-12(2-6-13)10-20(29,19(27)28)17(18(25)26)30-16(24)8-4-11-3-7-14(22)15(23)9-11/h1-9,17,21-23,29H,10H2,(H,25,26)(H,27,28)/b8-4+/t17-,20-/m1/s1
SMILES c1cc(ccc1C[C@@]([C@@H](C(=O)O)OC(=O)/C=C/c1ccc(c(c1)O)O)(C(=O)O)O)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   418.09 Volume:   398.901
?
Van der Waals volume.
Dense:   1.048 LogP:   1.455
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.692
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.705
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The logarithm of aqueous solubility value.
Rotatable Bonds:   9.0 Rigid Bonds:   16.0
TPSA:   181.82
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Topological Polar Surface Area.
 H-Bond Acceptor:   10.0
H-Bond Donor:   6.0 Rings:   2.0
Heavy Atoms:   10.0

MedChem Properties

QED Drug-Likeness Score:   0.204 GASA:   0.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.49 Fsp3:   0.15
MCE-18:   36.0
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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:   0.511 Fluc inhibitor:   0.92
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The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.02
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.496
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.59 Promiscuous compounds:   0.178

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -6.594 MDCK Permeability:   -5.082
Pgp-inhibitor:   0.0 Pgp-substrate:   0.014
PAMPA:   0.997
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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):   0.017
20% Bioavailability (F20%):   0.855 30% Bioavailability (F30%):   0.986
50% Bioavailability (F50%):   1.0

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.0 MRP1:   0.576
Plasma Protein Binding (PPB):   75.106% Volume Distribution (VD):   -0.512
Fu: 18.934%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.998
OATP1B3 inhibitor:   1.0 BCRP inhibitor:   0.001
BSEP inhibitor:   0.173

ADMET: Metabolism

CYP1A2-inhibitor:   0.0 CYP1A2-substrate:   0.0
CYP2C19-inhibitor:   0.0 CYP2C19-substrate:   0.004
CYP2C9-inhibitor:   0.205 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.001 CYP2D6-substrate:   0.0
CYP3A4-inhibitor:   0.0 CYP3A4-substrate:   0.853
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.935
HLM stability:   0.013
?
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):  4.55 Half-life (T1/2):  2.234

ADMET: Toxicity

hERG Blockers:  0.023 hERG Blockers (10um):  0.044
Human Hepatotoxicity (H-HT):  0.729 Drug-induced Liver Injury (DILI):  0.649
AMES Toxicity:  0.319 Rat Oral Acute Toxicity:  0.16
Maximum Recommended Daily Dose:  0.519 Skin Sensitization:  0.999
Carcinogencity:  0.114 Eye Corrosion:  0.016
Eye Irritation:  0.96 Respiratory Toxicity:  0.158
Drug-induced Neurotoxicity:  0.05 Ototoxicity:  0.86
Hematotoxicity:  0.067 Drug-induced Nephrotoxicity:  0.571
Genotoxicity:  0.991 RPMI-8226 Immunitoxicity:  0.007
A549 Cytotoxicity:  0.077 Hek293 Cytotoxicity:  0.061
BCF:   0.603
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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:   3.445
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.533
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.12
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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
NPO30530 Cimicifuga dahurica Species Ranunculaceae Eukaryota n.a. n.a. n.a. PMID[20192237]
NPO32999 cimicifuga heracleifolia Species Ranunculaceae Eukaryota n.a. n.a. n.a. PMID[20192237]
NPO30530 Cimicifuga dahurica Species Ranunculaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO30530 Cimicifuga dahurica Species Ranunculaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO30530 Cimicifuga dahurica Species Ranunculaceae Eukaryota 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

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT2 Others Unspecified n.a. IC50 = 153000.0 nM PMID[19114677]

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 NPC279676 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
0.8929 High Similarity NPC156709
0.8909 High Similarity NPC179505
0.8889 High Similarity NPC108553
0.8596 High Similarity NPC67349
0.7903 Intermediate Similarity NPC258671
0.7344 Intermediate Similarity NPC95498
0.7344 Intermediate Similarity NPC304956
0.7344 Intermediate Similarity NPC221383
0.7121 Intermediate Similarity NPC283081
0.697 Remote Similarity NPC143892
0.697 Remote Similarity NPC299090
0.697 Remote Similarity NPC246566
0.6557 Remote Similarity NPC198388
0.6545 Remote Similarity NPC217052
0.6545 Remote Similarity NPC329344
0.6545 Remote Similarity NPC237506
0.6545 Remote Similarity NPC32626
0.65 Remote Similarity NPC18074
0.65 Remote Similarity NPC5419
0.65 Remote Similarity NPC25581
0.65 Remote Similarity NPC61
0.6441 Remote Similarity NPC251407
0.6441 Remote Similarity NPC168653
0.6032 Remote Similarity NPC229264
0.6 Remote Similarity NPC132921
0.5821 Remote Similarity NPC477333
0.5735 Remote Similarity NPC289690
0.5634 Remote Similarity NPC53884
0.5595 Remote Similarity NPC223335
0.5595 Remote Similarity NPC40920
0.5588 Remote Similarity NPC471027
0.5349 Remote Similarity NPC44507
0.5231 Remote Similarity NPC470848
0.5224 Remote Similarity NPC13818
0.5224 Remote Similarity NPC219428
0.5205 Remote Similarity NPC477335
0.5139 Remote Similarity NPC38473
0.5075 Remote Similarity NPC475695
0.5075 Remote Similarity NPC610418

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC279676 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