NPASS Compound

Natural Product: NPC593604

Natural Product ID	NPC593604
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	CINCHONIDINE
IUPAC Name	(~{R})-4-quinolyl-[(2~{S},5~{R})-5-vinylquinuclidin-2-yl]methanol
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	n.a.
PubChem CID	n.a.
Chemical Classification	CHEMONTID:0000000 [Organic compounds]

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 44 47 0 0 0 0 0 0 0 0999 V2000 -3.4921 -2.3853 2.0902 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.5680 -1.7116 1.4353 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.7832 -0.3114 0.9963 C 0 0 1 0 0 0 0 0 0 0 0 0 -1.9467 0.6863 1.7415 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.2708 1.5260 0.7318 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.2389 2.1976 -0.0829 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.2065 1.2599 -0.7843 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.6787 -0.1498 -0.5046 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.2287 -0.1105 -0.9889 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3952 0.6194 0.0226 C 0 0 1 0 0 0 0 0 0 0 0 0 0.7872 1.3438 -0.5344 C 0 0 2 0 0 0 0 0 0 0 0 0 0.3971 2.3532 -1.4454 O 0 0 0 0 0 0 0 0 0 0 0 0 1.7380 0.4986 -1.2485 C 0 0 0 0 0 0 0 0 0 0 0 0 1.7262 0.3401 -2.6281 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6318 -0.4464 -3.2710 C 0 0 0 0 0 0 0 0 0 0 0 0 3.5768 -1.0977 -2.5477 N 0 0 0 0 0 0 0 0 0 0 0 0 3.6337 -0.9820 -1.2275 C 0 0 0 0 0 0 0 0 0 0 0 0 4.6251 -1.6797 -0.5481 C 0 0 0 0 0 0 0 0 0 0 0 0 4.7224 -1.5947 0.8217 C 0 0 0 0 0 0 0 0 0 0 0 0 3.8336 -0.8178 1.5016 C 0 0 0 0 0 0 0 0 0 0 0 0 2.8470 -0.1249 0.8131 C 0 0 0 0 0 0 0 0 0 0 0 0 2.7104 -0.1775 -0.5487 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.4300 -1.9045 2.3125 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3236 -3.3979 2.4020 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6216 -2.2336 1.2244 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.8558 -0.0513 1.2363 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.5126 1.3711 2.3825 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1234 0.1495 2.2716 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.7993 2.8816 0.6193 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.7690 2.8144 -0.8397 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.1760 1.3327 -0.2517 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2786 1.4667 -1.8646 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2593 -0.9217 -1.0055 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.8622 -1.1334 -1.1675 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2541 0.4524 -1.9534 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0457 -0.1457 0.7534 H 0 0 0 0 0 0 0 0 0 0 0 0 1.3078 1.8513 0.2999 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1590 2.5939 -2.0346 H 0 0 0 0 0 0 0 0 0 0 0 0 0.9347 0.8963 -3.1450 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5743 -0.5317 -4.3449 H 0 0 0 0 0 0 0 0 0 0 0 0 5.3312 -2.2993 -1.1115 H 0 0 0 0 0 0 0 0 0 0 0 0 5.4982 -2.1423 1.3389 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9012 -0.7437 2.5849 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1844 0.4591 1.4050 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 2 3 1 0 3 4 1 0 4 5 1 0 5 6 1 0 6 7 1 0 7 8 1 0 8 9 1 0 9 10 1 0 10 11 1 0 11 12 1 0 11 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 2 0 20 21 1 0 21 22 2 0 8 3 1 0 22 13 1 0 10 5 1 0 22 17 1 0 1 23 1 0 1 24 1 0 2 25 1 0 3 26 1 1 4 27 1 0 4 28 1 0 6 29 1 0 6 30 1 0 7 31 1 0 7 32 1 0 8 33 1 0 9 34 1 0 9 35 1 0 10 36 1 1 11 37 1 1 12 38 1 0 14 39 1 0 15 40 1 0 18 41 1 0 19 42 1 0 20 43 1 0 21 44 1 0 M END

Standard InCHIKey	KMPWYEUPVWOPIM-YNRGSOABSA-N
Standard InCHI	InChI=1S/C19H22N2O/c1-2-13-12-21-10-8-14(13)11-18(21)19(22)16-7-9-20-17-6-4-3-5-15(16)17/h2-7,9,13-14,18-19,22H,1,8,10-12H2/t13-,14?,18-,19+/m0/s1
SMILES	C=C[C@H]1CN2CCC1C[C@H]2[C@H](O)C1=CC=NC2=CC=CC=C12

Calculated Properties

Physi-Chem Properties

Molecular Weight:	294.17	Volume:	317.919 ? Van der Waals volume.
Dense:	0.925	LogP:	2.194 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.222 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-3.644 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	3.0	Rigid Bonds:	21.0
TPSA:	36.36 ? Topological Polar Surface Area.	H-Bond Acceptor:	3.0
H-Bond Donor:	1.0	Rings:	5.0
Heavy Atoms:	3.0

MedChem Properties

QED Drug-Likeness Score:	0.883	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	4.484	Fsp³:	0.421
MCE-18:	70.37 ? 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:	0.386	Fluc inhibitor:	0.0 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.101 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.057 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.004	Promiscuous compounds:	0.087

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.542	MDCK Permeability:	-4.767
Pgp-inhibitor:	0.837	Pgp-substrate:	0.826
PAMPA:	0.005 ? 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):	0.0
20% Bioavailability (F20%):	0.026	30% Bioavailability (F30%):	0.361
50% Bioavailability (F50%):	0.18

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.119	MRP1:	0.334
Plasma Protein Binding (PPB):	73.626%	Volume Distribution (VD):	0.273
Fu:	28.421% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.962
OATP1B3 inhibitor:	0.859	BCRP inhibitor:	0.489
BSEP inhibitor:	0.281

ADMET: Metabolism

CYP1A2-inhibitor:	0.159	CYP1A2-substrate:	0.024
CYP2C19-inhibitor:	0.965	CYP2C19-substrate:	0.083
CYP2C9-inhibitor:	0.02	CYP2C9-substrate:	0.956
CYP2D6-inhibitor:	0.192	CYP2D6-substrate:	0.006
CYP3A4-inhibitor:	0.309	CYP3A4-substrate:	0.942
CYP2B6-substrate:	0.001	CYP2C8-inhibitor:	0.792
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):

2.67

Half-life (T1/2):

2.263

ADMET: Toxicity

hERG Blockers:	0.255	hERG Blockers (10um):	0.524
Human Hepatotoxicity (H-HT):	0.578	Drug-induced Liver Injury (DILI):	0.173
AMES Toxicity:	0.357	Rat Oral Acute Toxicity:	0.536
Maximum Recommended Daily Dose:	0.555	Skin Sensitization:	0.238
Carcinogencity:	0.282	Eye Corrosion:	0.005
Eye Irritation:	0.658	Respiratory Toxicity:	0.683
Drug-induced Neurotoxicity:	0.752	Ototoxicity:	0.712
Hematotoxicity:	0.17	Drug-induced Nephrotoxicity:	0.512
Genotoxicity:	0.336	RPMI-8226 Immunitoxicity:	0.062
A549 Cytotoxicity:	0.237	Hek293 Cytotoxicity:	0.528
BCF:	1.419 ? 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:	3.466 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.664 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.201 ? 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
NPO25089	Cinchona calisaya	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[11992775]
NPO25089	Cinchona calisaya	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO30377	Cinchona ledgeriana	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO30377	Cinchona ledgeriana	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[HerDing]
NPO25089	Cinchona calisaya	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO30377	Cinchona ledgeriana	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCM_Taiwan]
NPO25089	Cinchona calisaya	Species	Rubiaceae	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 NPC593604 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	29282
0.1-0.2	20099
0.2-0.3	460
0.3-0.4	7
0.4-0.5	3
0.5-0.6	3
0.6-0.7	1
0.7-0.8	4
0.8-0.85	0
0.85-0.9	0
0.9-0.95	0
0.95-1	2

Similarity Score	Similarity Level	Natural Product ID
1.0	High Similarity	NPC203754
1.0	High Similarity	NPC150048
0.7206	Intermediate Similarity	NPC118832
0.7206	Intermediate Similarity	NPC329708
0.6324	Remote Similarity	NPC610661
0.5972	Remote Similarity	NPC165349
0.5972	Remote Similarity	NPC47059
0.5972	Remote Similarity	NPC610890

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC593604 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	4050
0.1-0.2	4847
0.2-0.3	241
0.3-0.4	2
0.4-0.5	0
0.5-0.6	3
0.6-0.7	3
0.7-0.8	4
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
0.7206	Intermediate Similarity	NPD4038	Phase 4
0.7206	Intermediate Similarity	NPD4039	Phase 4
0.7101	Intermediate Similarity	NPD4033	Approved
0.7101	Intermediate Similarity	NPD4037	Approved
0.6712	Remote Similarity	NPD31	Approved
0.6712	Remote Similarity	NPD32	Approved
0.6712	Remote Similarity	NPD4034	Approved
0.5972	Remote Similarity	NPD4122	Pre-clinical
0.5795	Remote Similarity	NPD4035	Approved
0.5765	Remote Similarity	NPD4036	Approved

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