Natural Product: NPC93411

Natural Product IDNPC93411
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Ajugarin I
IUPAC Name [(4R,4aR,5S,7R,8S,8aR)-5-acetyloxy-7,8-dimethyl-8-[2-(5-oxo-2H-furan-3-yl)ethyl]spiro[2,3,5,6,7,8a-hexahydro-1H-naphthalene-4,2'-oxirane]-4a-yl]methyl acetate
Synonyms Ajugarin-1
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL494606
PubChem CID 173866
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000264] Organic acids and derivatives
      • [CHEMONTID:0000265] Carboxylic acids and derivatives
        • [CHEMONTID:0001986] Tricarboxylic 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 RNYBNBANBCQZON-PGQNDPHJSA-N
Standard InCHI InChI=1S/C24H34O7/c1-15-10-20(31-17(3)26)24(14-29-16(2)25)19(6-5-8-23(24)13-30-23)22(15,4)9-7-18-11-21(27)28-12-18/h11,15,19-20H,5-10,12-14H2,1-4H3/t15-,19-,20+,22+,23+,24+/m1/s1
SMILES C[C@@H]1C[C@@H]([C@]2(COC(=O)C)[C@H](CCC[C@@]32CO3)[C@@]1(C)CCC1=CC(=O)OC1)OC(=O)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   434.23 Volume:   440.42
?
Van der Waals volume.
Dense:   0.986 LogP:   1.946
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.127
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.61
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   8.0 Rigid Bonds:   22.0
TPSA:   91.43
?
Topological Polar Surface Area.
 H-Bond Acceptor:   7.0
H-Bond Donor:   0.0 Rings:   4.0
Heavy Atoms:   7.0

MedChem Properties

QED Drug-Likeness Score:   0.36 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   5.216 Fsp3:   0.792
MCE-18:   99.628
?
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:   1
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.128 Fluc inhibitor:   0.001
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.019
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.003
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.351 Promiscuous compounds:   0.758

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.739 MDCK Permeability:   -4.621
Pgp-inhibitor:   0.318 Pgp-substrate:   0.062
PAMPA:   0.591
?
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%):   0.023 30% Bioavailability (F30%):   0.034
50% Bioavailability (F50%):   0.412

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.026 MRP1:   0.885
Plasma Protein Binding (PPB):   41.901% Volume Distribution (VD):   -0.39
Fu: 56.01%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   1.0
OATP1B3 inhibitor:   0.979 BCRP inhibitor:   0.163
BSEP inhibitor:   0.97

ADMET: Metabolism

CYP1A2-inhibitor:   0.202 CYP1A2-substrate:   0.029
CYP2C19-inhibitor:   0.182 CYP2C19-substrate:   0.0
CYP2C9-inhibitor:   0.003 CYP2C9-substrate:   0.049
CYP2D6-inhibitor:   0.0 CYP2D6-substrate:   0.071
CYP3A4-inhibitor:   0.748 CYP3A4-substrate:   0.72
CYP2B6-substrate:   0.001 CYP2C8-inhibitor:   0.998
HLM stability:   0.931
?
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):  5.674 Half-life (T1/2):  0.988

ADMET: Toxicity

hERG Blockers:  0.122 hERG Blockers (10um):  0.628
Human Hepatotoxicity (H-HT):  0.538 Drug-induced Liver Injury (DILI):  0.249
AMES Toxicity:  0.831 Rat Oral Acute Toxicity:  0.826
Maximum Recommended Daily Dose:  0.938 Skin Sensitization:  0.998
Carcinogencity:  0.845 Eye Corrosion:  0.0
Eye Irritation:  0.055 Respiratory Toxicity:  0.303
Drug-induced Neurotoxicity:  0.356 Ototoxicity:  0.223
Hematotoxicity:  0.743 Drug-induced Nephrotoxicity:  0.579
Genotoxicity:  0.991 RPMI-8226 Immunitoxicity:  0.269
A549 Cytotoxicity:  0.075 Hek293 Cytotoxicity:  0.406
BCF:   0.794
?
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:   3.97
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.945
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   5.306
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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
NPO19927 Ajuga remota Species n.a. n.a. n.a. n.a. n.a. PMID[12027771]
NPO19927 Ajuga remota Species n.a. n.a. n.a. n.a. n.a. Database[COCONUT]
NPO19927 Ajuga remota Species n.a. n.a. n.a. n.a. n.a. Database[TCMID]
NPO19927 Ajuga remota Species n.a. n.a. n.a. n.a. n.a. Database[TCM_Taiwan]
NPO19927 Ajuga remota Species n.a. n.a. 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
NPT762 Cell line A-431 Homo sapiens ED50 > 88.0 uM PMID[12027771]
NPT6 Organism Plasmodium falciparum Plasmodium falciparum IC50 = 23000.0 nM PMID[12027771]
NPT1192 Organism Spodoptera frugiperda Spodoptera frugiperda AFI = 47.0 % DOI[10.1016/S0040-4020(99)00612-2]
NPT1191 Organism Spodoptera exempta Spodoptera exempta AFI = 73.0 % DOI[10.1016/S0040-4020(99)00612-2]
NPT2 Others Unspecified n.a. Ratio > 4.0 n.a. PMID[12027771]

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 NPC93411 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
0.7 Intermediate Similarity NPC609068
0.625 Remote Similarity NPC479818
0.597 Remote Similarity NPC479821
0.5588 Remote Similarity NPC194132
0.5507 Remote Similarity NPC140277
0.5342 Remote Similarity NPC609123
0.5286 Remote Similarity NPC12297
0.5135 Remote Similarity NPC100912
0.5135 Remote Similarity NPC311241
0.5135 Remote Similarity NPC475380
0.5135 Remote Similarity NPC209297
0.5135 Remote Similarity NPC475446
0.507 Remote Similarity NPC479819

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC93411 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