Natural Product: NPC474324

Natural Product IDNPC474324
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 LMZHAKUXAHOCST-VNTMZGSJSA-N
IUPAC Name n.a.
Synonyms 1,2-Diacetoxylycorine; 1,2-Diacetyllycorine
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL465295
PubChem CID 10429288
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0001775] Amaryllidaceae alkaloids
        • [CHEMONTID:0004120] Lycorine-type amaryllidaceae alkaloids

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 LMZHAKUXAHOCST-VNTMZGSJSA-N
Standard InCHI InChI=1S/C20H21NO6/c1-10(22)26-17-5-12-3-4-21-8-13-6-15-16(25-9-24-15)7-14(13)18(19(12)21)20(17)27-11(2)23/h5-7,17-20H,3-4,8-9H2,1-2H3/t17-,18-,19+,20+/m0/s1
SMILES CC(=O)O[C@@H]1[C@@H](OC(=O)C)C=C2[C@@H]3[C@@H]1c1cc4OCOc4cc1CN3CC2

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   371.14 Volume:   359.613
?
Van der Waals volume.
Dense:   1.032 LogP:   0.981
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.373
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.952
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   25.0
TPSA:   74.3
?
Topological Polar Surface Area.
 H-Bond Acceptor:   7.0
H-Bond Donor:   0.0 Rings:   5.0
Heavy Atoms:   7.0

MedChem Properties

QED Drug-Likeness Score:   0.58 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.192 Fsp3:   0.5
MCE-18:   95.4
?
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:   0.494 Fluc inhibitor:   0.274
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.421
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.138
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.003 Promiscuous compounds:   0.435

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.8 MDCK Permeability:   -4.712
Pgp-inhibitor:   0.42 Pgp-substrate:   0.805
PAMPA:   0.11
?
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):   0.001
20% Bioavailability (F20%):   0.407 30% Bioavailability (F30%):   0.466
50% Bioavailability (F50%):   0.891

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.569 MRP1:   0.982
Plasma Protein Binding (PPB):   68.463% Volume Distribution (VD):   -0.006
Fu: 35.732%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.961
OATP1B3 inhibitor:   0.833 BCRP inhibitor:   0.007
BSEP inhibitor:   0.945

ADMET: Metabolism

CYP1A2-inhibitor:   0.4 CYP1A2-substrate:   0.192
CYP2C19-inhibitor:   0.786 CYP2C19-substrate:   0.005
CYP2C9-inhibitor:   0.372 CYP2C9-substrate:   1.0
CYP2D6-inhibitor:   0.806 CYP2D6-substrate:   0.983
CYP3A4-inhibitor:   0.006 CYP3A4-substrate:   0.998
CYP2B6-substrate:   0.019 CYP2C8-inhibitor:   0.044
HLM stability:   0.817
?
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):  6.944 Half-life (T1/2):  1.498

ADMET: Toxicity

hERG Blockers:  0.142 hERG Blockers (10um):  0.389
Human Hepatotoxicity (H-HT):  0.603 Drug-induced Liver Injury (DILI):  0.667
AMES Toxicity:  0.802 Rat Oral Acute Toxicity:  0.594
Maximum Recommended Daily Dose:  0.453 Skin Sensitization:  0.815
Carcinogencity:  0.844 Eye Corrosion:  0.004
Eye Irritation:  0.354 Respiratory Toxicity:  0.437
Drug-induced Neurotoxicity:  0.516 Ototoxicity:  0.374
Hematotoxicity:  0.621 Drug-induced Nephrotoxicity:  0.559
Genotoxicity:  0.99 RPMI-8226 Immunitoxicity:  0.062
A549 Cytotoxicity:  0.147 Hek293 Cytotoxicity:  0.196
BCF:   0.635
?
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:   3.458
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.975
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.475
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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
NPO25024 Lycoris traubii Species Amaryllidaceae Eukaryota n.a. n.a. n.a. PMID[19013823]
NPO33543 Brunsvigia littoralis Species Amaryllidaceae Eukaryota bulbs n.a. n.a. PMID[19299148]
NPO25024 Lycoris traubii Species Amaryllidaceae Eukaryota 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
NPT109 Individual protein Cytochrome P450 3A4 Homo sapiens Ki = 11000.0 nM PMID[17149857]
NPT109 Individual protein Cytochrome P450 3A4 Homo sapiens Ki = 10000.0 nM PMID[17438054]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT171 Cell line MRC5 Homo sapiens IC50 = 18.11 ug.mL-1 PMID[16180824]
NPT81 Cell line A549 Homo sapiens IC50 > 10000.0 nM PMID[19318121]
NPT170 Cell line SK-MEL-28 Homo sapiens IC50 > 10000.0 nM PMID[12617583]
NPT169 Cell line B16-F10 Mus musculus IC50 > 10000.0 nM PMID[12617583]
NPT844 Organism Trypanosoma brucei rhodesiense Trypanosoma brucei rhodesiense IC50 = 1.0 ug.mL-1 PMID[25771108]
NPT6 Organism Plasmodium falciparum Plasmodium falciparum IC50 = 1.0 ug.mL-1 PMID[12762792]
NPT6 Organism Plasmodium falciparum Plasmodium falciparum IC50 = 260.0 nM PMID[19738006]
NPT844 Organism Trypanosoma brucei rhodesiense Trypanosoma brucei rhodesiense IC50 >= 1.0 ug.mL-1 PMID[25771108]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. IC50 > 10000.0 nM PMID[19788245]
NPT580 Organism Trypanosoma cruzi Trypanosoma cruzi IC50 = 1.0 ug.mL-1 PMID[31515186]
NPT25178 Organism Edwardsiella ictaluri Edwardsiella ictaluri MIC > 37.0 ug.mL-1 PMID[29033234]
NPT16 Organism Staphylococcus aureus Staphylococcus aureus MIC > 37.0 ug.mL-1 PMID[29033234]
NPT471 Organism Trypanosoma brucei brucei Trypanosoma brucei brucei IC50 > 12.5 ug.mL-1 PMID[21604746]
NPT2 Others Unspecified n.a. Ratio IC50 < 1.4 n.a. PMID[18553926]
NPT485 Organism Plasmodium falciparum (isolate K1 / Thailand) Plasmodium falciparum K1 IC50 = 7.6 ug.mL-1 DOI[10.6019/CHEMBL1201861]
NPT2 Others Unspecified n.a. Ratio IC50 = 2.4 n.a. PMID[8350092]
NPT24393 Organism Flavobacterium columnare Flavobacterium columnare MIC = 4.0 ug.mL-1 PMID[29033234]
NPT24393 Organism Flavobacterium columnare Flavobacterium columnare MIC = 37.0 ug.mL-1 PMID[29033234]
NPT1019 Organism Trichomonas vaginalis Trichomonas vaginalis Activity = 19.0 % PMID[31515186]

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 NPC474324 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
0.8833 High Similarity NPC475845
0.8594 High Similarity NPC479863
0.8548 High Similarity NPC474708
0.7463 Intermediate Similarity NPC479869
0.7385 Intermediate Similarity NPC479870
0.726 Intermediate Similarity NPC479862
0.7164 Intermediate Similarity NPC237044
0.7 Intermediate Similarity NPC479859
0.6812 Remote Similarity NPC474325
0.662 Remote Similarity NPC475981
0.662 Remote Similarity NPC474745
0.6438 Remote Similarity NPC479857
0.6267 Remote Similarity NPC230098
0.6267 Remote Similarity NPC479864
0.6143 Remote Similarity NPC607721
0.5949 Remote Similarity NPC479866
0.5946 Remote Similarity NPC479858
0.5882 Remote Similarity NPC190332
0.5882 Remote Similarity NPC181653
0.5875 Remote Similarity NPC479865
0.5789 Remote Similarity NPC479860
0.5634 Remote Similarity NPC479856
0.5584 Remote Similarity NPC479867
0.5571 Remote Similarity NPC320104
0.557 Remote Similarity NPC479861
0.5139 Remote Similarity NPC246597
0.5125 Remote Similarity NPC479871

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC474324 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