Natural Product: NPC172765

Natural Product IDNPC172765
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 (S)-3,10-Dihydroxyl-2,9-Dimethoxytetrahyrdooxyprotoberberine
IUPAC Name (13aS)-2,9-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-3,10-diol
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL320397
PubChem CID 14378574
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000279] Alkaloids and derivatives
      • [CHEMONTID:0001909] Protoberberine alkaloids and derivatives

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 OPLHOPJAFJJLPX-HNNXBMFYSA-N
Standard InCHI InChI=1S/C19H21NO4/c1-23-18-9-13-12(8-17(18)22)5-6-20-10-14-11(7-15(13)20)3-4-16(21)19(14)24-2/h3-4,8-9,15,21-22H,5-7,10H2,1-2H3/t15-/m0/s1
SMILES COc1cc2c(cc1O)CCN1[C@H]2Cc2ccc(c(c2C1)OC)O

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   327.15 Volume:   333.293
?
Van der Waals volume.
Dense:   0.982 LogP:   1.175
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The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   1.303
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The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -2.304
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The logarithm of aqueous solubility value.
Rotatable Bonds:   2.0 Rigid Bonds:   21.0
TPSA:   62.16
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Topological Polar Surface Area.
 H-Bond Acceptor:   5.0
H-Bond Donor:   2.0 Rings:   4.0
Heavy Atoms:   5.0

MedChem Properties

QED Drug-Likeness Score:   0.888 GASA:   0.0
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GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.054 Fsp3:   0.368
MCE-18:   74.462
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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:   Rejected
Golden Triangle Rule:   Rejected BMS Rule:   0
Chelating Alert:   1 PAINS Alert:   0
Colloidal aggregators:   0.495 Fluc inhibitor:   0.058
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The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.567
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The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.502
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The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.002 Promiscuous compounds:   0.085

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.95 MDCK Permeability:   -4.727
Pgp-inhibitor:   0.001 Pgp-substrate:   0.927
PAMPA:   0.029
?
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):   0.005
20% Bioavailability (F20%):   0.701 30% Bioavailability (F30%):   0.919
50% Bioavailability (F50%):   0.994

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.177 MRP1:   0.974
Plasma Protein Binding (PPB):   75.628% Volume Distribution (VD):   -0.226
Fu: 23.679%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.992
OATP1B3 inhibitor:   0.99 BCRP inhibitor:   0.611
BSEP inhibitor:   0.394

ADMET: Metabolism

CYP1A2-inhibitor:   1.0 CYP1A2-substrate:   0.003
CYP2C19-inhibitor:   0.999 CYP2C19-substrate:   0.0
CYP2C9-inhibitor:   0.996 CYP2C9-substrate:   0.994
CYP2D6-inhibitor:   1.0 CYP2D6-substrate:   0.022
CYP3A4-inhibitor:   0.99 CYP3A4-substrate:   0.935
CYP2B6-substrate:   0.388 CYP2C8-inhibitor:   0.313
HLM stability:   0.701
?
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):  7.687 Half-life (T1/2):  1.841

ADMET: Toxicity

hERG Blockers:  0.333 hERG Blockers (10um):  0.629
Human Hepatotoxicity (H-HT):  0.535 Drug-induced Liver Injury (DILI):  0.076
AMES Toxicity:  0.573 Rat Oral Acute Toxicity:  0.719
Maximum Recommended Daily Dose:  0.789 Skin Sensitization:  0.848
Carcinogencity:  0.724 Eye Corrosion:  0.007
Eye Irritation:  0.57 Respiratory Toxicity:  0.951
Drug-induced Neurotoxicity:  0.654 Ototoxicity:  0.31
Hematotoxicity:  0.161 Drug-induced Nephrotoxicity:  0.452
Genotoxicity:  0.839 RPMI-8226 Immunitoxicity:  0.093
A549 Cytotoxicity:  0.341 Hek293 Cytotoxicity:  0.426
BCF:   1.331
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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:   3.947
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48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.043
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.468
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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
NPO19863 Micromelum ceylanicum Species Rutaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO20570 Esperiopsis digitata Species Esperiopsidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO16408 Grevillea hilliana Species Proteaceae 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
NPT1788 Individual protein Alpha-1a adrenergic receptor Homo sapiens Ki = 616.0 nM PMID[12825930]
NPT1789 Individual protein Alpha-1b adrenergic receptor Homo sapiens Ki = 360.0 nM PMID[12825930]
NPT221 Individual protein Alpha-1d adrenergic receptor Homo sapiens Ki = 25.0 nM PMID[12825930]
NPT1788 Individual protein Alpha-1a adrenergic receptor Homo sapiens Ki = 630.0 nM PMID[15664832]
NPT290 Individual protein Serotonin 2a (5-HT2a) receptor Homo sapiens Ki > 5000.0 nM PMID[23332346]
NPT242 Individual protein Dopamine D1 receptor Homo sapiens Ki = 200.0 nM PMID[23332346]
NPT243 Individual protein Dopamine D2 receptor Homo sapiens Ki = 113.0 nM PMID[23332346]
NPT242 Individual protein Dopamine D1 receptor Homo sapiens Inhibition = 98.3 % PMID[23332346]
NPT243 Individual protein Dopamine D2 receptor Homo sapiens Inhibition = 94.2 % PMID[23332346]
NPT290 Individual protein Serotonin 2a (5-HT2a) receptor Homo sapiens Inhibition = 84.0 % PMID[23332346]
NPT970 Protein family Adrenergic receptor alpha-1 Homo sapiens Ratio = 24.6 n.a. PMID[12825930]
NPT92 Individual protein Serotonin 1a (5-HT1a) receptor Homo sapiens Ki > 5000.0 nM PMID[23332346]
NPT92 Individual protein Serotonin 1a (5-HT1a) receptor Homo sapiens Inhibition = 76.7 % PMID[23332346]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference

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 NPC172765 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
0.8868 High Similarity NPC189266
0.8868 High Similarity NPC2413
0.8868 High Similarity NPC110416
0.8 Intermediate Similarity NPC39701
0.8 Intermediate Similarity NPC184026
0.7586 Intermediate Similarity NPC204828
0.7586 Intermediate Similarity NPC5238
0.7333 Intermediate Similarity NPC606650
0.7273 Intermediate Similarity NPC220858
0.7 Intermediate Similarity NPC312025
0.6897 Remote Similarity NPC151895
0.6721 Remote Similarity NPC295691
0.6721 Remote Similarity NPC207757
0.6721 Remote Similarity NPC54379
0.6379 Remote Similarity NPC88249
0.6119 Remote Similarity NPC232514
0.6032 Remote Similarity NPC249797
0.6032 Remote Similarity NPC193949
0.5645 Remote Similarity NPC191376
0.5625 Remote Similarity NPC469817
0.5484 Remote Similarity NPC210437
0.5484 Remote Similarity NPC16107
0.5484 Remote Similarity NPC106295
0.5397 Remote Similarity NPC51957
0.5385 Remote Similarity NPC276588
0.5385 Remote Similarity NPC127674
0.5385 Remote Similarity NPC278799
0.5373 Remote Similarity NPC264850
0.5172 Remote Similarity NPC192768
0.5077 Remote Similarity NPC321505
0.5077 Remote Similarity NPC179825
0.5075 Remote Similarity NPC216459
0.5075 Remote Similarity NPC41178
0.5075 Remote Similarity NPC138487

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC172765 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
0.5484 Remote Similarity NPD4584 Phase 2

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