Natural Product: NPC77435

Natural Product IDNPC77435
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Araplysillin 1
IUPAC Name (5R,6S)-N-[3-[4-(2-aminoethyl)-2,6-dibromophenoxy]propyl]-7,9-dibromo-6-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,7,9-triene-3-carboxamide
Synonyms Araplysillin 1
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL518416
PubChem CID 180014
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0002448] Benzenoids
      • [CHEMONTID:0002279] Benzene and substituted derivatives
        • [CHEMONTID:0000186] Phenethylamines

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 DJOILUOUAWXGIG-CTNGQTDRSA-N
Standard InCHI InChI=1S/C21H23Br4N3O5/c1-31-18-14(24)9-21(19(29)16(18)25)10-15(28-33-21)20(30)27-5-2-6-32-17-12(22)7-11(3-4-26)8-13(17)23/h7-9,19,29H,2-6,10,26H2,1H3,(H,27,30)/t19-,21+/m1/s1
SMILES COC1=C([C@H]([C@]2(C=C1Br)CC(=NO2)C(=O)NCCCOc1c(cc(CCN)cc1Br)Br)O)Br

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   712.84 Volume:   481.723
?
Van der Waals volume.
Dense:   1.48 LogP:   3.166
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.823
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -4.334
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The logarithm of aqueous solubility value.
Rotatable Bonds:   10.0 Rigid Bonds:   18.0
TPSA:   115.4
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Topological Polar Surface Area.
 H-Bond Acceptor:   8.0
H-Bond Donor:   4.0 Rings:   3.0
Heavy Atoms:   12.0

MedChem Properties

QED Drug-Likeness Score:   0.333 GASA:   1.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.509 Fsp3:   0.429
MCE-18:   92.4
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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:   Accepted BMS Rule:   0
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.985 Fluc inhibitor:   0.144
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The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.028
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.947
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.156 Promiscuous compounds:   0.07

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.013 MDCK Permeability:   -4.816
Pgp-inhibitor:   0.024 Pgp-substrate:   0.428
PAMPA:   0.075
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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):   0.004
20% Bioavailability (F20%):   0.001 30% Bioavailability (F30%):   0.011
50% Bioavailability (F50%):   0.664

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.009 MRP1:   0.998
Plasma Protein Binding (PPB):   91.649% Volume Distribution (VD):   -0.086
Fu: 9.307%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.996
OATP1B3 inhibitor:   0.982 BCRP inhibitor:   0.058
BSEP inhibitor:   0.997

ADMET: Metabolism

CYP1A2-inhibitor:   0.021 CYP1A2-substrate:   0.296
CYP2C19-inhibitor:   0.0 CYP2C19-substrate:   0.87
CYP2C9-inhibitor:   0.005 CYP2C9-substrate:   0.005
CYP2D6-inhibitor:   0.003 CYP2D6-substrate:   0.167
CYP3A4-inhibitor:   0.001 CYP3A4-substrate:   0.752
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   1.0
HLM stability:   0.0
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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):  1.186 Half-life (T1/2):  2.578

ADMET: Toxicity

hERG Blockers:  0.168 hERG Blockers (10um):  0.523
Human Hepatotoxicity (H-HT):  0.243 Drug-induced Liver Injury (DILI):  0.997
AMES Toxicity:  0.975 Rat Oral Acute Toxicity:  0.957
Maximum Recommended Daily Dose:  0.998 Skin Sensitization:  1.0
Carcinogencity:  0.969 Eye Corrosion:  0.066
Eye Irritation:  0.454 Respiratory Toxicity:  0.923
Drug-induced Neurotoxicity:  0.872 Ototoxicity:  0.444
Hematotoxicity:  0.004 Drug-induced Nephrotoxicity:  0.347
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.102
A549 Cytotoxicity:  0.105 Hek293 Cytotoxicity:  0.829
BCF:   1.625
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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:   4.265
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.746
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   5.034
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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
NPO33394 druinella sp. Species n.a. n.a. n.a. Fujian, China n.a. PMID[12502317]
NPO40724 Pseudoceratina cf. verrucosa Strain Pseudoceratinidae Eukaryota n.a. n.a. n.a. PMID[28085276]
NPO40724 Pseudoceratina cf. verrucosa Strain Pseudoceratinidae Eukaryota n.a. n.a. n.a. Database[COCONUT]

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
NPT740 Individual protein Beta-secretase 1 Homo sapiens Inhibition = 27.0 % PMID[22037378]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT81 Cell line A549 Homo sapiens Activity = 16.0 % PMID[10096871]
NPT81 Cell line A549 Homo sapiens Activity = 17.0 % Open TG-GATES in vivo data: Hematology
NPT83 Cell line MCF7 Homo sapiens Activity = 71.0 % PMID[18329887]
NPT83 Cell line MCF7 Homo sapiens Activity = 36.0 % PMID[9358643]
NPT179 Cell line A2780 Homo sapiens ID50 = 18.57 ug ml-1 PMID[12852764]
NPT111 Cell line K562 Homo sapiens ID50 = 27.93 ug ml-1 PMID[20937779]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 14.0 % PMID[26711149]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 8.0 % PMID[26711149]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 22.0 % PMID[26711149]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 11.0 % PMID[26711149]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 32.0 % PMID[26711149]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Activity = 30.0 % PMID[26711149]

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 NPC77435 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 NPC259071
0.85 High Similarity NPC202866
0.8235 Intermediate Similarity NPC611077
0.8148 Intermediate Similarity NPC483876
0.8148 Intermediate Similarity NPC600925
0.8095 Intermediate Similarity NPC603425
0.7907 Intermediate Similarity NPC606574
0.7727 Intermediate Similarity NPC607100
0.7586 Intermediate Similarity NPC480151
0.7294 Intermediate Similarity NPC607066
0.7234 Intermediate Similarity NPC227953
0.7234 Intermediate Similarity NPC603698
0.6939 Remote Similarity NPC606635
0.6591 Remote Similarity NPC487915
0.6526 Remote Similarity NPC609979
0.6517 Remote Similarity NPC487914
0.6517 Remote Similarity NPC489611
0.6517 Remote Similarity NPC604329
0.6163 Remote Similarity NPC487872
0.6163 Remote Similarity NPC608122
0.6105 Remote Similarity NPC489612
0.6042 Remote Similarity NPC174607
0.5955 Remote Similarity NPC487873
0.5897 Remote Similarity NPC1702
0.5876 Remote Similarity NPC121571
0.5876 Remote Similarity NPC8093
0.575 Remote Similarity NPC158672
0.5714 Remote Similarity NPC147847
0.5542 Remote Similarity NPC487917
0.5402 Remote Similarity NPC473262
0.5402 Remote Similarity NPC202166
0.5281 Remote Similarity NPC473261
0.5281 Remote Similarity NPC300912
0.5222 Remote Similarity NPC313173
0.5217 Remote Similarity NPC66855
0.5217 Remote Similarity NPC181086
0.5213 Remote Similarity NPC608121
0.5125 Remote Similarity NPC308571
0.5111 Remote Similarity NPC145149
0.5109 Remote Similarity NPC470886
0.5109 Remote Similarity NPC600759
0.5062 Remote Similarity NPC128877
0.5053 Remote Similarity NPC477220

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC77435 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