Natural Product: NPC473105

Natural Product IDNPC473105
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Isovoacristine
IUPAC Name n.a.
Synonyms Isovoacristine
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL360973
PubChem CID 12304498
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0002748] Ibogan-type 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 XGWIRMWTCWJZPG-ZHBRIVESSA-N
Standard InCHI InChI=1S/C22H28N2O4/c1-12(25)17-8-13-10-22(21(26)28-3)19-16(6-7-24(11-13)20(17)22)15-5-4-14(27-2)9-18(15)23-19/h4-5,9,12-13,17,20,23,25H,6-8,10-11H2,1-3H3/t12-,13-,17+,20-,22+/m0/s1
SMILES CC(C1CC2CC3(C1N(C2)CCC4=C3NC5=C4C=CC(=C5)OC)C(=O)OC)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   384.2 Volume:   390.258
?
Van der Waals volume.
Dense:   0.984 LogP:   2.32
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.43
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.432
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   24.0
TPSA:   74.79
?
Topological Polar Surface Area.
 H-Bond Acceptor:   6.0
H-Bond Donor:   2.0 Rings:   6.0
Heavy Atoms:   6.0

MedChem Properties

QED Drug-Likeness Score:   0.794 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   5.232 Fsp3:   0.591
MCE-18:   101.914
?
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:   0.101 Fluc inhibitor:   0.004
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.798
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.336
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.001 Promiscuous compounds:   0.059

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -5.148 MDCK Permeability:   -5.088
Pgp-inhibitor:   0.024 Pgp-substrate:   0.17
PAMPA:   0.094
?
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):   0.003
20% Bioavailability (F20%):   0.045 30% Bioavailability (F30%):   0.104
50% Bioavailability (F50%):   0.934

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.303 MRP1:   0.997
Plasma Protein Binding (PPB):   57.782% Volume Distribution (VD):   0.136
Fu: 44.744%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.617
OATP1B3 inhibitor:   0.995 BCRP inhibitor:   0.844
BSEP inhibitor:   0.994

ADMET: Metabolism

CYP1A2-inhibitor:   1.0 CYP1A2-substrate:   0.0
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.0
CYP2C9-inhibitor:   0.775 CYP2C9-substrate:   0.79
CYP2D6-inhibitor:   0.999 CYP2D6-substrate:   0.906
CYP3A4-inhibitor:   0.567 CYP3A4-substrate:   0.0
CYP2B6-substrate:   0.903 CYP2C8-inhibitor:   0.039
HLM stability:   0.948
?
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):  9.632 Half-life (T1/2):  1.434

ADMET: Toxicity

hERG Blockers:  0.498 hERG Blockers (10um):  0.656
Human Hepatotoxicity (H-HT):  0.606 Drug-induced Liver Injury (DILI):  0.314
AMES Toxicity:  0.608 Rat Oral Acute Toxicity:  0.742
Maximum Recommended Daily Dose:  0.96 Skin Sensitization:  0.021
Carcinogencity:  0.626 Eye Corrosion:  0.0
Eye Irritation:  0.008 Respiratory Toxicity:  0.903
Drug-induced Neurotoxicity:  0.619 Ototoxicity:  0.96
Hematotoxicity:  0.18 Drug-induced Nephrotoxicity:  0.665
Genotoxicity:  0.782 RPMI-8226 Immunitoxicity:  0.082
A549 Cytotoxicity:  0.203 Hek293 Cytotoxicity:  0.685
BCF:   0.677
?
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:   3.543
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.33
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.558
?
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
NPO32495 tabernaemontana calcarea Species Apocynaceae Eukaryota n.a. Madagascar rainforest n.a. PMID[12713407]

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
NPT91 Cell line KB Homo sapiens IC50 > 25.0 ug.mL-1 PMID[16934977]
NPT91 Cell line KB Homo sapiens IC50 = 18.8 ug.mL-1 DrugMatrix in vitro pharmacology data
NPT179 Cell line A2780 Homo sapiens IC50 = 9.6 ug.mL-1 PMID[17269825]

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 NPC473105 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
0.8451 Intermediate Similarity NPC473041
0.8 Intermediate Similarity NPC474192
0.7838 Intermediate Similarity NPC485936
0.7838 Intermediate Similarity NPC485937
0.7407 Intermediate Similarity NPC485947
0.7179 Intermediate Similarity NPC485887
0.6709 Remote Similarity NPC96321
0.6709 Remote Similarity NPC111993
0.6667 Remote Similarity NPC485941
0.6538 Remote Similarity NPC329858
0.642 Remote Similarity NPC330009
0.6375 Remote Similarity NPC482061
0.6024 Remote Similarity NPC469928
0.5865 Remote Similarity NPC485966
0.5843 Remote Similarity NPC485946
0.5765 Remote Similarity NPC485884
0.5301 Remote Similarity NPC329747
0.5234 Remote Similarity NPC485933
0.5234 Remote Similarity NPC485970
0.5185 Remote Similarity NPC475666
0.5057 Remote Similarity NPC475910
0.5047 Remote Similarity NPC485969

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC473105 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