Natural Product: NPC260434

Natural Product IDNPC260434
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Harmic Acid Methyl Ester
IUPAC Name methyl 7-methoxy-9H-pyrido[3,4-b]indole-1-carboxylate
Synonyms Harmic Acid Methyl Ester
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL1957116
PubChem CID 57391302
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0001140] Harmala 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 GGTFWDPYRXONGD-UHFFFAOYSA-N
Standard InCHI InChI=1S/C14H12N2O3/c1-18-8-3-4-9-10-5-6-15-13(14(17)19-2)12(10)16-11(9)7-8/h3-7,16H,1-2H3
SMILES COc1ccc2c(c1)[nH]c1c2ccnc1C(=O)OC

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   256.08 Volume:   254.94
?
Van der Waals volume.
Dense:   1.004 LogP:   2.426
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   2.563
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -4.204
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   3.0 Rigid Bonds:   16.0
TPSA:   64.21
?
Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   1.0 Rings:   3.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.715 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   2.212 Fsp3:   0.143
MCE-18:   16.0
?
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:   0.177 Fluc inhibitor:   0.666
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.924
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.285
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.031 Promiscuous compounds:   0.916

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.594 MDCK Permeability:   -4.351
Pgp-inhibitor:   0.274 Pgp-substrate:   0.151
PAMPA:   0.134
?
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):   0.118
20% Bioavailability (F20%):   0.182 30% Bioavailability (F30%):   0.345
50% Bioavailability (F50%):   0.901

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.058 MRP1:   0.905
Plasma Protein Binding (PPB):   85.866% Volume Distribution (VD):   -0.023
Fu: 12.492%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.98
OATP1B3 inhibitor:   0.998 BCRP inhibitor:   0.977
BSEP inhibitor:   0.969

ADMET: Metabolism

CYP1A2-inhibitor:   0.917 CYP1A2-substrate:   0.002
CYP2C19-inhibitor:   0.03 CYP2C19-substrate:   0.002
CYP2C9-inhibitor:   0.468 CYP2C9-substrate:   0.494
CYP2D6-inhibitor:   0.472 CYP2D6-substrate:   0.716
CYP3A4-inhibitor:   0.006 CYP3A4-substrate:   0.0
CYP2B6-substrate:   0.002 CYP2C8-inhibitor:   0.545
HLM stability:   0.625
?
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):  9.332 Half-life (T1/2):  0.657

ADMET: Toxicity

hERG Blockers:  0.354 hERG Blockers (10um):  0.564
Human Hepatotoxicity (H-HT):  0.571 Drug-induced Liver Injury (DILI):  0.959
AMES Toxicity:  0.834 Rat Oral Acute Toxicity:  0.562
Maximum Recommended Daily Dose:  0.729 Skin Sensitization:  0.127
Carcinogencity:  0.806 Eye Corrosion:  0.001
Eye Irritation:  0.932 Respiratory Toxicity:  0.86
Drug-induced Neurotoxicity:  0.792 Ototoxicity:  0.62
Hematotoxicity:  0.547 Drug-induced Nephrotoxicity:  0.885
Genotoxicity:  0.527 RPMI-8226 Immunitoxicity:  0.111
A549 Cytotoxicity:  0.264 Hek293 Cytotoxicity:  0.459
BCF:   0.515
?
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:   3.225
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.468
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.9
?
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
NPO503 Trigonostemon lii Species Euphorbiaceae Eukaryota leaves n.a. n.a. PMID[22342628]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota Seeds n.a. n.a. PMID[28128938]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota n.a. n.a. n.a. PMID[38971075]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota n.a. n.a. n.a. PMID[6736972]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO1085 Peganum harmala Species Nitrariaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO503 Trigonostemon lii Species Euphorbiaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO1085 Peganum harmala Species Nitrariaceae 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

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 > 40000.0 nM DrugMatrix in vivo data: Pathology
NPT659 Cell line SMMC-7721 Homo sapiens IC50 > 40000.0 nM PMID[19318257]
NPT81 Cell line A549 Homo sapiens IC50 > 40000.0 nM PMID[2478667]
NPT83 Cell line MCF7 Homo sapiens IC50 > 40000.0 nM PMID[27189674]
NPT660 Cell line SW480 Homo sapiens IC50 > 40000.0 nM PubChem BioAssay data set
NPT116 Cell line HL-60 Homo sapiens IC50 > 10000.0 nM PMID[28128938]
NPT306 Cell line PC-3 Homo sapiens IC50 > 10000.0 nM PMID[28128938]
NPT515 Cell line SGC-7901 Homo sapiens IC50 > 10000.0 nM PMID[28128938]

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 NPC260434 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
0.74 Intermediate Similarity NPC232727
0.7115 Intermediate Similarity NPC122436
0.7115 Intermediate Similarity NPC479097
0.6981 Remote Similarity NPC479095
0.6852 Remote Similarity NPC146472
0.6731 Remote Similarity NPC266249
0.6066 Remote Similarity NPC60621
0.5873 Remote Similarity NPC101350
0.569 Remote Similarity NPC123839
0.5522 Remote Similarity NPC235685
0.5286 Remote Similarity NPC91868

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC260434 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