NPASS Compound

Natural Product: NPC15864

Natural Product ID	NPC15864
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	(1R,2S,5S)-3-Azabicyclo[3.1.0]Hexane-2-Carboxylic Acid
IUPAC Name	(1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL1311694
PubChem CID	11073435 11869789
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0004603] Organic oxygen compounds [CHEMONTID:0000323] Organooxygen compounds [CHEMONTID:0000011] Carbohydrates and carbohydrate conjugates [CHEMONTID:0000215] Sugar acids and derivatives [CHEMONTID:0001366] Sugar amino acids and derivatives [CHEMONTID:0001698] Bicyclic amino acids 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	JBDOTWVUXVXVDR-WDCZJNDASA-N
Standard InCHI	InChI=1S/C6H9NO2/c8-6(9)5-4-1-3(4)2-7-5/h3-5,7H,1-2H2,(H,8,9)/t3-,4-,5+/m1/s1
SMILES	C1[C@@H]2CN[C@@H]([C@H]12)C(=O)O

Calculated Properties

Physi-Chem Properties

Molecular Weight:	127.06	Volume:	121.16 ? Van der Waals volume.
Dense:	1.049	LogP:	-1.45 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	-0.138 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-0.028 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	1.0	Rigid Bonds:	8.0
TPSA:	49.33 ? Topological Polar Surface Area.	H-Bond Acceptor:	3.0
H-Bond Donor:	2.0	Rings:	2.0
Heavy Atoms:	3.0

MedChem Properties

QED Drug-Likeness Score:	0.507	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	3.965	Fsp³:	0.833
MCE-18:	29.091 ? 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:	Accepted	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.024	Fluc inhibitor:	0.0 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.047 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.01 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.16	Promiscuous compounds:	0.455

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.883	MDCK Permeability:	-5.345
Pgp-inhibitor:	0.001	Pgp-substrate:	0.085
PAMPA:	0.964 ? 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):	0.225
20% Bioavailability (F20%):	0.291	30% Bioavailability (F30%):	0.418
50% Bioavailability (F50%):	0.453

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.291	MRP1:	0.724
Plasma Protein Binding (PPB):	12.812%	Volume Distribution (VD):	-0.503
Fu:	88.615% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.641
OATP1B3 inhibitor:	0.78	BCRP inhibitor:	0.023
BSEP inhibitor:	0.028

ADMET: Metabolism

CYP1A2-inhibitor:	0.0	CYP1A2-substrate:	0.0
CYP2C19-inhibitor:	0.004	CYP2C19-substrate:	0.0
CYP2C9-inhibitor:	0.022	CYP2C9-substrate:	0.002
CYP2D6-inhibitor:	0.023	CYP2D6-substrate:	0.0
CYP3A4-inhibitor:	0.001	CYP3A4-substrate:	0.006
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.001
HLM stability:	0.004 ? 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):

1.382

Half-life (T1/2):

2.212

ADMET: Toxicity

hERG Blockers:	0.026	hERG Blockers (10um):	0.087
Human Hepatotoxicity (H-HT):	0.381	Drug-induced Liver Injury (DILI):	0.177
AMES Toxicity:	0.344	Rat Oral Acute Toxicity:	0.352
Maximum Recommended Daily Dose:	0.063	Skin Sensitization:	0.818
Carcinogencity:	0.087	Eye Corrosion:	0.811
Eye Irritation:	0.974	Respiratory Toxicity:	0.322
Drug-induced Neurotoxicity:	0.084	Ototoxicity:	0.283
Hematotoxicity:	0.411	Drug-induced Nephrotoxicity:	0.607
Genotoxicity:	0.116	RPMI-8226 Immunitoxicity:	0.041
A549 Cytotoxicity:	0.005	Hek293 Cytotoxicity:	0.018
BCF:	0.209 ? 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:	2.87 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.193 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	3.406 ? 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
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	DOI[10.1016/j.jarmap.2018.11.004]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	DOI[10.1016/S0031-9422(00)98060-9]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	DOI[10.1042/bst0160071]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[11559179]
NPO18777	Endiandra anthropophagorum	Species	Lauraceae	Eukaryota	n.a.	Australian	n.a.	PMID[17583952]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[18001808]
NPO16051	Beilschmiedia erythrophloia	Species	Lauraceae	Eukaryota	Roots	n.a.	n.a.	PMID[19072217]
NPO18777	Endiandra anthropophagorum	Species	Lauraceae	Eukaryota	n.a.	Australian rainforest	n.a.	PMID[19138858]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[20954721]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[23479199]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[36500609]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO4518.1	Saccharothrix mutabilis subsp. capreolus	Subspecies	Pseudonocardiaceae	Bacteria	n.a.	n.a.	n.a.	Database[COCONUT]
NPO16051	Beilschmiedia erythrophloia	Species	Lauraceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO19179	Laminaria ochroleuca	Species	Laminariaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO17364	Engelhardtia chrysolepis	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[COCONUT]
NPO18503	Eugenia kurzii	Species	Myrtaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO5074	Coryneum modonium	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[COCONUT]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[HerDing]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCM_Taiwan]
NPO9807	Fuscoporia gilva	Species	Hymenochaetaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO17694	Nicotiana tabacum	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO4518.1	Saccharothrix mutabilis subsp. capreolus	Subspecies	Pseudonocardiaceae	Bacteria	n.a.	n.a.	n.a.	Database[UNPD]
NPO19179	Laminaria ochroleuca	Species	Laminariaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO7424	Mitragyna javanica	Species	Rubiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO12002	Amoora dasyclada	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[UNPD]
NPO16051	Beilschmiedia erythrophloia	Species	Lauraceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO5074	Coryneum modonium	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[UNPD]
NPO12637	Carpinus japonica	Species	Betulaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO18777	Endiandra anthropophagorum	Species	Lauraceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO15019	Pteridium caudatum	Species	Dennstaedtiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO13217	Helichrysum cameroonense	Species	Asteraceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO17364	Engelhardtia chrysolepis	n.a.	n.a.	n.a.	n.a.	n.a.	n.a.	Database[UNPD]
NPO26440	Cedrela glaziovii	Species	Meliaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO18503	Eugenia kurzii	Species	Myrtaceae	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

Activity Type	# Activity
Potency	7
Ki	1
pKi	1

Activity Type	# Activity
Individual protein	8
Organism	1

Molecular-level activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT152	Individual protein	Nuclear factor erythroid 2-related factor 2	Homo sapiens	Potency	n.a.	14581.0	nM	PubChem BioAssay data set
NPT1006	Individual protein	Proton-coupled amino acid transporter 1	Homo sapiens	Ki	=	2700000.0	nM	PMID[21955456]
NPT1006	Individual protein	Proton-coupled amino acid transporter 1	Homo sapiens	pKi	=	-0.43	mM	PMID[21955456]
NPT11	Individual protein	Guanine nucleotide-binding protein G(s), subunit alpha	Homo sapiens	Potency	n.a.	50118.7	nM	PubChem BioAssay data set
NPT54	Individual protein	Nonstructural protein 1	Influenza A virus	Potency	=	10000.0	nM	PubChem BioAssay data set
NPT52	Individual protein	Pyruvate kinase isozymes M1/M2	Homo sapiens	Potency	=	28183.8	nM	PubChem BioAssay data set
NPT5	Individual protein	Histone-lysine N-methyltransferase, H3 lysine-9 specific 3	Homo sapiens	Potency	n.a.	89125.1	nM	PubChem BioAssay data set

In vitro activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT6	Organism	Plasmodium falciparum	Plasmodium falciparum	Potency	n.a.	18526.0	nM	PubChem BioAssay data set

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 NPC15864 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	40908
0.1-0.2	8161
0.2-0.3	634
0.3-0.4	101
0.4-0.5	49
0.5-0.6	5
0.6-0.7	0
0.7-0.8	0
0.8-0.85	0
0.85-0.9	0
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.5417	Remote Similarity	NPC155156
0.5417	Remote Similarity	NPC602396
0.5185	Remote Similarity	NPC11433
0.5185	Remote Similarity	NPC302003
0.5185	Remote Similarity	NPC245346

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC15864 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	6560
0.1-0.2	2308
0.2-0.3	225
0.3-0.4	46
0.4-0.5	10
0.5-0.6	1
0.6-0.7	0
0.7-0.8	0
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
0.5185	Remote Similarity	NPD8865	Phase 2

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