Natural Product: NPC474771

Natural Product IDNPC474771
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Curvularin
IUPAC Name 13,15-dihydroxy-5-methyl-4-oxabicyclo[10.4.0]hexadeca-1(12),13,15-triene-3,11-dione
Synonyms Curvularin
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL482052
PubChem CID 296197
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000261] Phenylpropanoids and polyketides
      • [CHEMONTID:0000147] Macrolides and analogues

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 VDUIGYAPSXCJFC-UHFFFAOYSA-N
Standard InCHI InChI=1S/C16H20O5/c1-10-5-3-2-4-6-13(18)16-11(8-15(20)21-10)7-12(17)9-14(16)19/h7,9-10,17,19H,2-6,8H2,1H3
SMILES CC1CCCCCC(=O)C2=C(CC(=O)O1)C=C(C=C2O)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   292.13 Volume:   298.948
?
Van der Waals volume.
Dense:   0.977 LogP:   1.781
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.071
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.467
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   0.0 Rigid Bonds:   19.0
TPSA:   83.83
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   2.0 Rings:   2.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.718 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.483 Fsp3:   0.5
MCE-18:   46.583
?
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:   0.077 Fluc inhibitor:   0.252
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.195
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.303
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.355 Promiscuous compounds:   0.156

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.756 MDCK Permeability:   -4.708
Pgp-inhibitor:   0.523 Pgp-substrate:   0.002
PAMPA:   0.049
?
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):   0.002
20% Bioavailability (F20%):   0.002 30% Bioavailability (F30%):   0.075
50% Bioavailability (F50%):   0.495

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.114 MRP1:   0.891
Plasma Protein Binding (PPB):   96.978% Volume Distribution (VD):   -0.3
Fu: 3.088%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.678
OATP1B3 inhibitor:   0.988 BCRP inhibitor:   0.413
BSEP inhibitor:   0.85

ADMET: Metabolism

CYP1A2-inhibitor:   0.998 CYP1A2-substrate:   0.01
CYP2C19-inhibitor:   0.019 CYP2C19-substrate:   0.007
CYP2C9-inhibitor:   0.046 CYP2C9-substrate:   0.028
CYP2D6-inhibitor:   0.003 CYP2D6-substrate:   0.881
CYP3A4-inhibitor:   0.009 CYP3A4-substrate:   0.002
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.297
HLM stability:   0.995
?
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):  1.671 Half-life (T1/2):  1.372

ADMET: Toxicity

hERG Blockers:  0.06 hERG Blockers (10um):  0.404
Human Hepatotoxicity (H-HT):  0.522 Drug-induced Liver Injury (DILI):  0.636
AMES Toxicity:  0.421 Rat Oral Acute Toxicity:  0.144
Maximum Recommended Daily Dose:  0.546 Skin Sensitization:  0.977
Carcinogencity:  0.398 Eye Corrosion:  0.397
Eye Irritation:  0.992 Respiratory Toxicity:  0.539
Drug-induced Neurotoxicity:  0.503 Ototoxicity:  0.292
Hematotoxicity:  0.211 Drug-induced Nephrotoxicity:  0.71
Genotoxicity:  0.159 RPMI-8226 Immunitoxicity:  0.105
A549 Cytotoxicity:  0.155 Hek293 Cytotoxicity:  0.247
BCF:   0.496
?
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:   3.035
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.24
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.598
?
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
NPO33114 penicillium sumatrense ma-92 Species Aspergillaceae Eukaryota rhizosphere of the mangrove Lumnitzera racemosa n.a. n.a. PMID[24195466]

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
NPT367 Cell line MDA-N Homo sapiens GI50 n.a. 100000.0 nM PMID[25127167]
NPT370 Cell line NCI-H23 Homo sapiens GI50 n.a. 48865.24 nM PMID[17958396]
NPT368 Cell line SN12C Homo sapiens GI50 n.a. 100000.0 nM PubChem BioAssay data set
NPT369 Cell line ACHN Homo sapiens GI50 n.a. 100000.0 nM PMID[23317013]
NPT371 Cell line UO-31 Homo sapiens GI50 n.a. 44977.99 nM PMID[24063582]
NPT372 Cell line HOP-92 Homo sapiens GI50 n.a. 100000.0 nM PMID[11575950]
NPT116 Cell line HL-60 Homo sapiens GI50 n.a. 54325.03 nM PMID[21513293]
NPT90 Cell line DU-145 Homo sapiens GI50 n.a. 100000.0 nM PMID[6834379]
NPT374 Cell line SF-539 Homo sapiens GI50 n.a. 100000.0 nM PMID[18611050]
NPT373 Cell line SK-MEL-5 Homo sapiens GI50 n.a. 100000.0 nM PMID[11325240]
NPT375 Cell line Malme-3M Homo sapiens GI50 n.a. 100000.0 nM PMID[11412985]
NPT111 Cell line K562 Homo sapiens GI50 n.a. 41591.06 nM PMID[20061160]
NPT376 Cell line A498 Homo sapiens GI50 n.a. 100000.0 nM PMID[15217280]
NPT377 Cell line OVCAR-3 Homo sapiens GI50 n.a. 96605.09 nM PMID[26465972]
NPT379 Cell line HOP-62 Homo sapiens GI50 n.a. 100000.0 nM DrugMatrix in vitro pharmacology data
NPT112 Cell line MOLT-4 Homo sapiens GI50 n.a. 73790.42 nM PMID[15568795]
NPT378 Cell line NCI/ADR-RES Homo sapiens GI50 n.a. 100000.0 nM PMID[22230050]
NPT380 Cell line U-251 Homo sapiens GI50 n.a. 100000.0 nM PMID[19691309]
NPT381 Cell line OVCAR-8 Homo sapiens GI50 n.a. 100000.0 nM PMID[12762789]
NPT382 Cell line OVCAR-5 Homo sapiens GI50 n.a. 100000.0 nM PMID[20361780]
NPT383 Cell line SNB-19 Homo sapiens GI50 n.a. 100000.0 nM PMID[12502328]
NPT385 Cell line SR Homo sapiens GI50 n.a. 44463.13 nM Open TG-GATES in vivo data: Biochemistry
NPT82 Cell line MDA-MB-231 Homo sapiens GI50 n.a. 100000.0 nM PMID[17571903]
NPT384 Cell line TK-10 Homo sapiens GI50 n.a. 90157.11 nM PMID[18077363]
NPT323 Cell line SW-620 Homo sapiens GI50 n.a. 100000.0 nM Open TG-GATES in vivo data: Hematology
NPT455 Cell line NCI-H522 Homo sapiens GI50 n.a. 100000.0 nM PMID[20934335]
NPT387 Cell line M14 Homo sapiens GI50 n.a. 100000.0 nM DrugMatrix in vivo data: Pathology
NPT386 Cell line KM12 Homo sapiens GI50 n.a. 100000.0 nM PMID[17132069]
NPT388 Cell line NCI-H322M Homo sapiens GI50 n.a. 100000.0 nM PMID[16643057]
NPT389 Cell line RPMI-8226 Homo sapiens GI50 n.a. 67764.15 nM PMID[11429990]
NPT456 Cell line OVCAR-4 Homo sapiens GI50 n.a. 100000.0 nM PMID[24223237]
NPT390 Cell line LOX IMVI Homo sapiens GI50 n.a. 43853.07 nM PMID[9051914]
NPT457 Cell line BT-549 Homo sapiens GI50 n.a. 54075.43 nM PMID[26003344]
NPT147 Cell line SK-MEL-2 Homo sapiens GI50 n.a. 76559.66 nM PMID[19615900]
NPT81 Cell line A549 Homo sapiens GI50 n.a. 100000.0 nM PMID[23398362]
NPT392 Cell line SNB-75 Homo sapiens GI50 n.a. 57411.65 nM PMID[19433554]
NPT391 Cell line HCC 2998 Homo sapiens GI50 n.a. 100000.0 nM DrugMatrix in vivo data: Pathology
NPT148 Cell line HCT-15 Homo sapiens GI50 n.a. 100000.0 nM PubChem BioAssay data set
NPT393 Cell line HCT-116 Homo sapiens GI50 n.a. 100000.0 nM PMID[23294419]
NPT395 Cell line SF-268 Homo sapiens GI50 n.a. 100000.0 nM PMID[10891117]
NPT394 Cell line EKVX Homo sapiens GI50 n.a. 61517.69 nM DOI[10.6019/CHEMBL1201861]
NPT83 Cell line MCF7 Homo sapiens GI50 n.a. 100000.0 nM PMID[12604693]
NPT306 Cell line PC-3 Homo sapiens GI50 n.a. 66834.39 nM DOI[10.6019/CHEMBL1201861]
NPT146 Cell line SK-OV-3 Homo sapiens GI50 n.a. 100000.0 nM PMID[22560833]
NPT396 Cell line T47D Homo sapiens GI50 n.a. 59156.16 nM PMID[24491225]
NPT398 Cell line UACC-62 Homo sapiens GI50 n.a. 100000.0 nM PMID[12088422]
NPT397 Cell line NCI-H460 Homo sapiens GI50 n.a. 98174.79 nM PMID[9917320]
NPT308 Cell line CAKI-1 Homo sapiens GI50 n.a. 100000.0 nM PMID[10096871]
NPT400 Cell line MDA-MB-435 Homo sapiens GI50 n.a. 100000.0 nM PMID[15711537]
NPT399 Cell line SF-295 Homo sapiens GI50 n.a. 94841.85 nM PMID[26854381]
NPT458 Cell line IGROV-1 Homo sapiens GI50 n.a. 100000.0 nM PMID[22409377]
NPT402 Cell line Hs-578T Homo sapiens GI50 n.a. 100000.0 nM PMID[18321710]
NPT401 Cell line 786-0 Homo sapiens GI50 n.a. 100000.0 nM Open TG-GATES in vivo data: Hematology
NPT404 Cell line CCRF-CEM Homo sapiens GI50 n.a. 74301.91 nM PMID[25819096]
NPT403 Cell line UACC-257 Homo sapiens GI50 n.a. 55590.43 nM PMID[23286240]
NPT405 Cell line NCI-H226 Homo sapiens GI50 n.a. 100000.0 nM PMID[20485427]
NPT139 Cell line HT-29 Homo sapiens GI50 n.a. 100000.0 nM PMID[23398362]
NPT170 Cell line SK-MEL-28 Homo sapiens GI50 n.a. 100000.0 nM PMID[17988094]
NPT406 Cell line RXF 393 Homo sapiens GI50 n.a. 100000.0 nM DOI[10.6019/CHEMBL1201861]
NPT407 Cell line COLO 205 Homo sapiens GI50 n.a. 100000.0 nM PMID[9213587]

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
- Cucumis sativus LD50 = 21.0 ug ml-1 Open TG-GATES in vivo data: Organ Weight

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 NPC474771 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 NPC178467
0.7451 Intermediate Similarity NPC605699
0.7222 Intermediate Similarity NPC474849
0.7222 Intermediate Similarity NPC65837
0.7222 Intermediate Similarity NPC149372
0.7091 Intermediate Similarity NPC475974
0.7037 Intermediate Similarity NPC177307
0.7037 Intermediate Similarity NPC9121
0.6607 Remote Similarity NPC354984
0.6364 Remote Similarity NPC474655
0.6094 Remote Similarity NPC55092
0.5821 Remote Similarity NPC275837
0.5821 Remote Similarity NPC213224
0.56 Remote Similarity NPC164870
0.5156 Remote Similarity NPC489318

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC474771 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