Natural Product: NPC156485

Natural Product IDNPC156485
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Micheliolide
IUPAC Name (3aS,9R,9aS,9bS)-9-hydroxy-6,9-dimethyl-3-methylidene-4,5,7,8,9a,9b-hexahydro-3aH-azuleno[4,5-b]furan-2-one
Synonyms Micheliolide
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL449579
PubChem CID 442279
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000002] Organoheterocyclic compounds
      • [CHEMONTID:0000050] Lactones
        • [CHEMONTID:0001245] Gamma butyrolactones

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 RDJAFOWISVMOJY-PWNZVWSESA-N
Standard InCHI InChI=1S/C15H20O3/c1-8-4-5-11-9(2)14(16)18-13(11)12-10(8)6-7-15(12,3)17/h11-13,17H,2,4-7H2,1,3H3/t11-,12-,13-,15+/m0/s1
SMILES CC1=C2CC[C@@]([C@@H]2[C@@H]2[C@@H](CC1)C(=C)C(=O)O2)(C)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   248.14 Volume:   260.788
?
Van der Waals volume.
Dense:   0.952 LogP:   1.527
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.659
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.664
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   0.0 Rigid Bonds:   17.0
TPSA:   46.53
?
Topological Polar Surface Area.
 H-Bond Acceptor:   3.0
H-Bond Donor:   1.0 Rings:   3.0
Heavy Atoms:   3.0

MedChem Properties

QED Drug-Likeness Score:   0.406 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.471 Fsp3:   0.667
MCE-18:   50.16
?
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:   1
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.203 Fluc inhibitor:   0.0
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.022
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.007
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.666 Promiscuous compounds:   0.506

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.105 MDCK Permeability:   -4.891
Pgp-inhibitor:   0.813 Pgp-substrate:   0.052
PAMPA:   0.521
?
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):   0.031
20% Bioavailability (F20%):   0.117 30% Bioavailability (F30%):   0.607
50% Bioavailability (F50%):   0.94

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.0 MRP1:   0.491
Plasma Protein Binding (PPB):   64.403% Volume Distribution (VD):   0.092
Fu: 27.634%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.999
OATP1B3 inhibitor:   0.999 BCRP inhibitor:   0.408
BSEP inhibitor:   0.998

ADMET: Metabolism

CYP1A2-inhibitor:   0.052 CYP1A2-substrate:   0.054
CYP2C19-inhibitor:   0.202 CYP2C19-substrate:   0.006
CYP2C9-inhibitor:   0.036 CYP2C9-substrate:   0.005
CYP2D6-inhibitor:   0.001 CYP2D6-substrate:   0.356
CYP3A4-inhibitor:   0.473 CYP3A4-substrate:   0.634
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.322
HLM stability:   0.11
?
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):  9.294 Half-life (T1/2):  1.665

ADMET: Toxicity

hERG Blockers:  0.024 hERG Blockers (10um):  0.181
Human Hepatotoxicity (H-HT):  0.773 Drug-induced Liver Injury (DILI):  0.489
AMES Toxicity:  0.423 Rat Oral Acute Toxicity:  0.254
Maximum Recommended Daily Dose:  0.376 Skin Sensitization:  0.911
Carcinogencity:  0.627 Eye Corrosion:  0.226
Eye Irritation:  0.902 Respiratory Toxicity:  0.19
Drug-induced Neurotoxicity:  0.311 Ototoxicity:  0.58
Hematotoxicity:  0.539 Drug-induced Nephrotoxicity:  0.698
Genotoxicity:  0.347 RPMI-8226 Immunitoxicity:  0.076
A549 Cytotoxicity:  0.107 Hek293 Cytotoxicity:  0.191
BCF:   0.645
?
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:   3.346
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.909
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.175
?
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
NPO31577.1 Michelia compressa var. formosana Varieties Magnoliaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO31577.1 Michelia compressa var. formosana Varieties Magnoliaceae 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
NPT25490 Single protein NACHT, LRR and PYD domains-containing protein 3 Mus musculus IC50 = 2300.0 nM PMID[32738997]
NPT584 Individual protein NACHT, LRR and PYD domains-containing protein 3 Homo sapiens IC50 = 5900.0 nM PMID[32738997]
NPT52 Individual protein Pyruvate kinase isozymes M1/M2 Homo sapiens EC50 = 6.0 nM PMID[29641204]
NPT52 Individual protein Pyruvate kinase isozymes M1/M2 Homo sapiens Activity n.a. n.a. n.a. PMID[34726055]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT116 Cell line HL-60 Homo sapiens IC50 = 5500.0 nM PMID[22985027]
NPT1182 Cell line J774.A1 Mus musculus TC50 = 21.9 uM PMID[32738997]
NPT2615 Cell line HEK-293T Homo sapiens TC50 = 51.7 uM PMID[32738997]
NPT88 Organism Mycobacterium tuberculosis Mycobacterium tuberculosis MIC = 50.0 ug.mL-1 PMID[9784148]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. CFU = 0.0 n.a. PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. CFU = 4.5 n.a. PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. FC = 5.3 n.a. PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. FC = 3.2 n.a. PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 2.3 % PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 4.2 % PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 8.4 % PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 11.7 % PMID[22985027]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. IC50 = 6200.0 nM PMID[22985027]
NPT2 Others Unspecified n.a. Activity = 1.42 % PMID[22985027]
NPT2 Others Unspecified n.a. Activity = 24.2 % PMID[22985027]
NPT2 Others Unspecified n.a. Activity = 69.4 % PMID[22985027]
NPT2 Others Unspecified n.a. Activity = 0.127 % PMID[22985027]

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 NPC156485 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
0.56 Remote Similarity NPC245665
0.549 Remote Similarity NPC224652
0.5306 Remote Similarity NPC79549
0.5192 Remote Similarity NPC67493
0.5094 Remote Similarity NPC181151
0.5094 Remote Similarity NPC258216

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC156485 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