Natural Product: NPC242945

Natural Product IDNPC242945
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Kolavenic Acid
IUPAC Name (E)-5-[(1S,2R,4aR,8aR)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]-3-methylpent-2-enoic acid
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL1517738
PubChem CID 6441458
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000012] Lipids and lipid-like molecules
      • [CHEMONTID:0000259] Prenol lipids
        • [CHEMONTID:0001551] Diterpenoids
          • [CHEMONTID:0001757] Colensane and clerodane diterpenoids

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 NLVMTSRTOGOFQD-MWRQYBNOSA-N
Standard InCHI InChI=1S/C20H32O2/c1-14(13-18(21)22)9-11-19(4)16(3)10-12-20(5)15(2)7-6-8-17(19)20/h7,13,16-17H,6,8-12H2,1-5H3,(H,21,22)/b14-13+/t16-,17-,19+,20+/m1/s1
SMILES OC(=O)/C=C(/CC[C@@]1(C)[C@H](C)CC[C@@]2([C@@H]1CCC=C2C)C)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   304.24 Volume:   347.034
?
Van der Waals volume.
Dense:   0.877 LogP:   4.635
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   3.38
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -3.935
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   4.0 Rigid Bonds:   13.0
TPSA:   37.3
?
Topological Polar Surface Area.
 H-Bond Acceptor:   2.0
H-Bond Donor:   1.0 Rings:   2.0
Heavy Atoms:   2.0

MedChem Properties

QED Drug-Likeness Score:   0.542 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   4.175 Fsp3:   0.75
MCE-18:   41.771
?
MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.
 Lipinski Rule-of-5:   Rejected
Pfizer Rule:   Accepted GSK Rule:   Accepted
Golden Triangle Rule:   Rejected BMS Rule:   0
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.332 Fluc inhibitor:   0.001
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.005
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.001
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.956 Promiscuous compounds:   0.288

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.696 MDCK Permeability:   -4.574
Pgp-inhibitor:   0.059 Pgp-substrate:   0.001
PAMPA:   0.736
?
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%):   0.05 30% Bioavailability (F30%):   0.009
50% Bioavailability (F50%):   0.201

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.007 MRP1:   0.984
Plasma Protein Binding (PPB):   90.307% Volume Distribution (VD):   -0.463
Fu: 11.18%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.996
OATP1B3 inhibitor:   0.837 BCRP inhibitor:   0.023
BSEP inhibitor:   0.983

ADMET: Metabolism

CYP1A2-inhibitor:   0.006 CYP1A2-substrate:   0.047
CYP2C19-inhibitor:   1.0 CYP2C19-substrate:   0.679
CYP2C9-inhibitor:   0.747 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.013 CYP2D6-substrate:   0.0
CYP3A4-inhibitor:   0.995 CYP3A4-substrate:   0.972
CYP2B6-substrate:   0.997 CYP2C8-inhibitor:   1.0
HLM stability:   0.347
?
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):  4.66 Half-life (T1/2):  0.545

ADMET: Toxicity

hERG Blockers:  0.009 hERG Blockers (10um):  0.028
Human Hepatotoxicity (H-HT):  0.694 Drug-induced Liver Injury (DILI):  0.652
AMES Toxicity:  0.14 Rat Oral Acute Toxicity:  0.223
Maximum Recommended Daily Dose:  0.191 Skin Sensitization:  0.877
Carcinogencity:  0.601 Eye Corrosion:  0.617
Eye Irritation:  0.971 Respiratory Toxicity:  0.735
Drug-induced Neurotoxicity:  0.087 Ototoxicity:  0.439
Hematotoxicity:  0.609 Drug-induced Nephrotoxicity:  0.833
Genotoxicity:  0.222 RPMI-8226 Immunitoxicity:  0.023
A549 Cytotoxicity:  0.03 Hek293 Cytotoxicity:  0.042
BCF:   1.846
?
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:   4.262
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   5.426
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48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   4.969
?
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
NPO21774 Macaranga monandra Species Euphorbiaceae Eukaryota n.a. n.a. n.a. PMID[14664515]
NPO21774 Macaranga monandra Species Euphorbiaceae 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
NPT151 Individual protein 15-hydroxyprostaglandin dehydrogenase [NAD+] Homo sapiens Potency = 28183.8 nM PMID[21493075]
NPT2892 Individual protein X-box-binding protein 1 Homo sapiens IC50 > 10000.0 nM PMID[25597012]
NPT2893 Individual protein DNA damage-inducible transcript 3 protein Mus musculus IC50 > 9680.0 nM PMID[27015610]
NPT154 Individual protein Mothers against decapentaplegic homolog 3 Homo sapiens Potency n.a. 22387.2 nM PMID[23327905]
NPT10 Individual protein Geminin Homo sapiens Potency n.a. 5173.5 nM PMID[26073007]
NPT101 Individual protein Glucagon-like peptide 1 receptor Homo sapiens Potency n.a. 11220.2 nM PMID[19053514]
NPT1043 Individual protein Glycoprotein hormones alpha chain Homo sapiens Potency n.a. 316.2 nM PMID[18183025]
NPT161 Individual protein Rap guanine nucleotide exchange factor 4 Homo sapiens Potency n.a. 31622.8 nM PMID[20625154]
NPT803 Individual protein Flap endonuclease 1 Homo sapiens Potency n.a. 89125.1 nM PMID[17190469]
NPT9 Individual protein DNA polymerase eta Homo sapiens Potency n.a. 89125.1 nM PMID[20625154]
NPT444 Individual protein Ubiquitin carboxyl-terminal hydrolase 1 Homo sapiens Potency n.a. 44668.4 nM PMID[22748705]
NPT831 Individual protein Serine/threonine-protein kinase PLK1 Homo sapiens Potency n.a. 13371.4 nM PMID[20014752]
NPT446 Individual protein Rap guanine nucleotide exchange factor 3 Homo sapiens Potency n.a. 44668.4 nM PMID[22409377]
NPT821 Individual protein Werner syndrome ATP-dependent helicase Homo sapiens Potency n.a. 63095.7 nM PMID[11908979]
NPT755 Individual protein Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 Homo sapiens Potency n.a. 28183.8 nM PMID[22686608]
NPT49 Individual protein DNA-(apurinic or apyrimidinic site) lyase Homo sapiens Potency n.a. 7943.3 nM PMID[15679330]

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT65 Cell line HepG2 Homo sapiens Potency n.a. 14125.4 nM PMID[18280170]
NPT82 Cell line MDA-MB-231 Homo sapiens IC50 = 271800.0 nM PMID[31753800]
NPT1374 Cell line WI-38 Homo sapiens IC50 = 265000.0 nM PMID[31753800]
NPT850 Organism Diaporthe ampelina Diaporthe ampelina GI = 50.0 % PMID[23282106]
NPT635 Organism Botryotinia fuckeliana Botryotinia fuckeliana GI = 23.0 % PubChem BioAssay data set
NPT851 Organism Colletotrichum fragariae Colletotrichum fragariae IZ = 9.0 mm PMID[15787442]
NPT851 Organism Colletotrichum fragariae Colletotrichum fragariae IZ = 8.5 mm PMID[15787442]
NPT851 Organism Colletotrichum fragariae Colletotrichum fragariae IZ = 5.0 mm PMID[9868159]
NPT852 Organism Phomopsis obscurans Phomopsis obscurans GI = 26.0 % PubChem BioAssay data set
NPT2 Others Unspecified n.a. Potency = 29092.9 nM PMID[1732519]
NPT2 Others Unspecified n.a. Potency n.a. 20596.2 nM PMID[18197599]
NPT562 Organism Colletotrichum gloeosporioides Colletotrichum gloeosporioides IZ = 9.5 mm PMID[9868159]
NPT2 Others Unspecified n.a. Potency n.a. 19952.6 nM PMID[10425119]

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 NPC242945 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 NPC481396
0.7447 Intermediate Similarity NPC481394
0.7447 Intermediate Similarity NPC481395
0.6531 Remote Similarity NPC109576
0.6531 Remote Similarity NPC56747
0.6531 Remote Similarity NPC19907
0.6226 Remote Similarity NPC604999
0.62 Remote Similarity NPC272849
0.6136 Remote Similarity NPC606666
0.5833 Remote Similarity NPC607973
0.58 Remote Similarity NPC476945
0.537 Remote Similarity NPC473251
0.537 Remote Similarity NPC42586
0.5185 Remote Similarity NPC175145
0.5185 Remote Similarity NPC475069
0.5185 Remote Similarity NPC484939
0.5179 Remote Similarity NPC472440
0.5091 Remote Similarity NPC306951
0.5091 Remote Similarity NPC481392
0.5091 Remote Similarity NPC481393

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC242945 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