NPASS Compound

Natural Product: NPC476581

Natural Product ID	NPC476581
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Palmatine Trifluoroacetate
IUPAC Name	2,3,9,10-tetramethoxy-5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium;2,2,2-trifluoroacetate
Synonyms	Palmatine Trifluoroacetate
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	n.a.
PubChem CID	49850521
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

RDKit 3D 55 57 0 0 0 0 0 0 0 0999 V2000 6.7872 1.6956 -0.4809 C 0 0 0 0 0 0 0 0 0 0 0 0 5.9212 0.6056 -0.6814 O 0 0 0 0 0 0 0 0 0 0 0 0 4.5426 0.6998 -0.5037 C 0 0 0 0 0 0 0 0 0 0 0 0 3.7270 -0.3855 -0.7084 C 0 0 0 0 0 0 0 0 0 0 0 0 2.3497 -0.2813 -0.5280 C 0 0 0 0 0 0 0 0 0 0 0 0 1.5530 -1.3629 -0.7363 C 0 0 0 0 0 0 0 0 0 0 0 0 0.2176 -1.2634 -0.5626 N 0 0 0 0 0 4 0 0 0 0 0 0 -0.3704 -0.1201 -0.1808 C 0 0 0 0 0 0 0 0 0 0 0 0 0.4043 0.9865 0.0335 C 0 0 0 0 0 0 0 0 0 0 0 0 1.7627 0.8982 -0.1428 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6092 1.9771 0.0567 C 0 0 0 0 0 0 0 0 0 0 0 0 3.9823 1.8846 -0.1200 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.8083 -0.0563 0.1514 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.4325 1.1679 0.4042 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.8108 1.2223 0.5831 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.5150 0.0417 0.5014 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.9127 -1.1682 0.2555 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.5377 -1.2164 0.0804 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.8170 -2.4932 -0.0569 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.6340 -2.3851 -0.9211 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.8885 0.0647 0.6729 O 0 0 0 0 0 0 0 0 0 0 0 0 -6.7142 -1.0549 0.6148 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.5087 2.3904 0.8371 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.9034 3.6538 0.9430 C 0 0 0 0 0 0 0 0 0 0 0 0 4.2350 -1.6117 -1.0975 O 0 0 0 0 0 0 0 0 0 0 0 0 4.6449 -2.6072 -0.1764 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8381 -0.0251 -0.0534 C 0 0 0 0 0 0 0 0 0 0 0 0 1.4938 -0.8749 -0.7063 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.6323 -0.0330 0.0307 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0907 1.1684 -0.4862 F 0 0 0 0 0 0 0 0 0 0 0 0 -1.0312 -0.1462 1.3647 F 0 0 0 0 0 0 0 0 0 0 0 0 -1.1618 -1.0272 -0.7451 F 0 0 0 0 0 0 0 0 0 0 0 0 1.5842 0.9380 0.5956 O 0 0 0 0 0 1 0 0 0 0 0 0 7.8255 1.3706 -0.4554 H 0 0 0 0 0 0 0 0 0 0 0 0 6.6298 2.4337 -1.3003 H 0 0 0 0 0 0 0 0 0 0 0 0 6.4729 2.1620 0.4981 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9338 -2.3265 -1.0414 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0359 1.9096 0.3360 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1597 2.9187 0.3620 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5769 2.7692 0.0545 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9025 2.0807 0.4667 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.4575 -2.1062 0.1887 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.4241 -2.7550 0.9876 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.5143 -3.3229 -0.3616 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.0023 -2.2041 -1.9780 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0332 -3.3325 -0.9648 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.7536 -0.7168 0.8630 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.4657 -1.8271 1.3903 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.7552 -1.5450 -0.3713 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.5923 4.2984 1.5334 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9399 3.5220 1.4795 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7491 4.0432 -0.0917 H 0 0 0 0 0 0 0 0 0 0 0 0 5.7204 -2.5918 0.0290 H 0 0 0 0 0 0 0 0 0 0 0 0 4.0623 -2.4716 0.7543 H 0 0 0 0 0 0 0 0 0 0 0 0 4.3605 -3.5905 -0.5974 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 2 3 1 0 3 4 2 0 4 5 1 0 5 6 2 0 6 7 1 0 7 8 2 0 8 9 1 0 9 10 2 0 10 11 1 0 11 12 2 0 8 13 1 0 13 14 2 0 14 15 1 0 15 16 2 0 16 17 1 0 17 18 2 0 18 19 1 0 19 20 1 0 16 21 1 0 21 22 1 0 15 23 1 0 23 24 1 0 4 25 1 0 25 26 1 0 27 28 2 0 27 29 1 0 29 30 1 0 29 31 1 0 29 32 1 0 27 33 1 0 12 3 1 0 10 5 1 0 20 7 1 0 18 13 1 0 1 34 1 0 1 35 1 0 1 36 1 0 6 37 1 0 9 38 1 0 11 39 1 0 12 40 1 0 14 41 1 0 17 42 1 0 19 43 1 0 19 44 1 0 20 45 1 0 20 46 1 0 22 47 1 0 22 48 1 0 22 49 1 0 24 50 1 0 24 51 1 0 24 52 1 0 26 53 1 0 26 54 1 0 26 55 1 0 M CHG 2 7 1 33 -1 M END

Standard InCHIKey	VTKAIZPURDIHOT-UHFFFAOYSA-M
Standard InCHI	InChI=1S/C21H22NO4.C2HF3O2/c1-23-18-6-5-13-9-17-15-11-20(25-3)19(24-2)10-14(15)7-8-22(17)12-16(13)21(18)26-4;3-2(4,5)1(6)7/h5-6,9-12H,7-8H2,1-4H3;(H,6,7)/q+1;/p-1
SMILES	COC1=C(C2=C[N+]3=C(C=C2C=C1)C4=CC(=C(C=C4CC3)OC)OC)OC.C(=O)(C(F)(F)F)[O-]

Calculated Properties

Physi-Chem Properties

Molecular Weight:	352.15	Volume:	363.931 ? Van der Waals volume.
Dense:	0.968	LogP:	2.893 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	3.099 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-4.82 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	4.0	Rigid Bonds:	21.0
TPSA:	40.8 ? Topological Polar Surface Area.	H-Bond Acceptor:	5.0
H-Bond Donor:	0.0	Rings:	4.0
Heavy Atoms:	5.0

MedChem Properties

QED Drug-Likeness Score:	0.675	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	2.62	Fsp³:	0.286
MCE-18:	47.259 ? 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:	0.758	Fluc inhibitor:	0.034 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.71 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.494 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.021	Promiscuous compounds:	0.603

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.042	MDCK Permeability:	-4.751
Pgp-inhibitor:	0.05	Pgp-substrate:	1.0
PAMPA:	0.043 ? 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):	0.589
20% Bioavailability (F20%):	0.961	30% Bioavailability (F30%):	0.846
50% Bioavailability (F50%):	0.998

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.002	MRP1:	0.871
Plasma Protein Binding (PPB):	55.463%	Volume Distribution (VD):	-0.02
Fu:	34.649% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.779
OATP1B3 inhibitor:	0.948	BCRP inhibitor:	0.995
BSEP inhibitor:	0.993

ADMET: Metabolism

CYP1A2-inhibitor:	0.992	CYP1A2-substrate:	0.0
CYP2C19-inhibitor:	0.992	CYP2C19-substrate:	0.0
CYP2C9-inhibitor:	0.023	CYP2C9-substrate:	0.014
CYP2D6-inhibitor:	0.289	CYP2D6-substrate:	0.018
CYP3A4-inhibitor:	0.548	CYP3A4-substrate:	0.077
CYP2B6-substrate:	0.535	CYP2C8-inhibitor:	0.053
HLM stability:	0.784 ? 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):

8.128

Half-life (T1/2):

1.984

ADMET: Toxicity

hERG Blockers:	0.275	hERG Blockers (10um):	0.477
Human Hepatotoxicity (H-HT):	0.123	Drug-induced Liver Injury (DILI):	0.091
AMES Toxicity:	0.293	Rat Oral Acute Toxicity:	0.866
Maximum Recommended Daily Dose:	0.881	Skin Sensitization:	0.968
Carcinogencity:	0.655	Eye Corrosion:	0.059
Eye Irritation:	0.977	Respiratory Toxicity:	0.932
Drug-induced Neurotoxicity:	0.087	Ototoxicity:	0.065
Hematotoxicity:	0.071	Drug-induced Nephrotoxicity:	0.081
Genotoxicity:	0.954	RPMI-8226 Immunitoxicity:	0.118
A549 Cytotoxicity:	0.005	Hek293 Cytotoxicity:	0.483
BCF:	2.299 ? 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:	4.228 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.339 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.726 ? 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
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	stem wood	n.a.	DOI[10.1021/np100247r]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[10395501]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[10425140]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	Fruits	n.a.	n.a.	PMID[15568797]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	stem	Taipei Botanical Garden, Taipei, Taiwan, China	2006-MAR	PMID[20828184]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	fruits	n.a.	n.a.	PMID[25499882]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[9584397]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[9599260]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	Database[HerDing]
NPO6333	Annona glabra	Species	Annonaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO6333	Annona glabra	Species	Annonaceae	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

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

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 NPC476581 and all remaining natural products in the NPASS database.
● The right table: Most similar natural products (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	32987
0.1-0.2	16679
0.2-0.3	175
0.3-0.4	2
0.4-0.5	2
0.5-0.6	4
0.6-0.7	5
0.7-0.8	2
0.8-0.85	0
0.85-0.9	2
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.8814	High Similarity	NPC36229
0.8644	High Similarity	NPC16452
0.7576	Intermediate Similarity	NPC296482
0.7424	Intermediate Similarity	NPC53069
0.7313	Intermediate Similarity	NPC202768
0.6765	Remote Similarity	NPC202605
0.6667	Remote Similarity	NPC96405
0.6522	Remote Similarity	NPC171409
0.6212	Remote Similarity	NPC607600
0.6061	Remote Similarity	NPC4071
0.5857	Remote Similarity	NPC31930
0.5342	Remote Similarity	NPC313189
0.52	Remote Similarity	NPC112206
0.5128	Remote Similarity	NPC481435

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC476581 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	5696
0.1-0.2	3437
0.2-0.3	15
0.3-0.4	0
0.4-0.5	0
0.5-0.6	0
0.6-0.7	0
0.7-0.8	2
0.8-0.85	0
0.85-0.9	0
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Drug ID	Developmental Stage
0.7576	Intermediate Similarity	NPD3815	Phase 1
0.7424	Intermediate Similarity	NPD3816	Phase 3

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