NPASS Compound

Natural Product: NPC259071

Natural Product ID	NPC259071
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Araplysillin I
IUPAC Name	(5S,6R)-N-[3-[4-(2-aminoethyl)-2,6-dibromophenoxy]propyl]-7,9-dibromo-6-hydroxy-8-methoxy-1-oxa-2-azaspiro[4.5]deca-2,7,9-triene-3-carboxamide
Synonyms	Araplysillin I
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL2047175
PubChem CID	23426312
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0002448] Benzenoids [CHEMONTID:0002279] Benzene and substituted derivatives [CHEMONTID:0000186] Phenethylamines

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 56 58 0 0 0 0 0 0 0 0999 V2000 -9.8077 -1.2779 0.0152 C 0 0 0 0 0 0 0 0 0 0 0 0 -8.4572 -1.5485 -0.2969 O 0 0 0 0 0 0 0 0 0 0 0 0 -7.4452 -0.6111 -0.1447 C 0 0 0 0 0 0 0 0 0 0 0 0 -7.3353 0.4662 -0.9013 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.2569 1.4626 -0.7371 C 0 0 1 0 0 0 0 0 0 0 0 0 -5.2831 1.1862 0.3432 C 0 0 1 0 0 0 0 0 0 0 0 0 -5.4940 -0.0336 1.1234 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.4680 -0.8727 0.9269 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.6350 -2.4361 2.0183 Br 0 0 0 0 0 0 0 0 0 0 0 0 -3.8571 1.1003 -0.2127 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.0599 1.5524 0.9481 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.8053 2.2367 1.7174 N 0 0 0 0 0 0 0 0 0 0 0 0 -5.1021 2.3245 1.2092 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.6334 1.2385 1.1441 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.0636 1.6761 2.1656 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.9139 0.4646 0.2117 N 0 0 0 0 0 0 0 0 0 0 0 0 0.4850 0.1293 0.3550 C 0 0 0 0 0 0 0 0 0 0 0 0 1.3023 1.4116 0.3955 C 0 0 0 0 0 0 0 0 0 0 0 0 2.7498 0.9834 0.5438 C 0 0 0 0 0 0 0 0 0 0 0 0 3.0637 0.1775 -0.5928 O 0 0 0 0 0 0 0 0 0 0 0 0 4.3510 -0.3241 -0.6590 C 0 0 0 0 0 0 0 0 0 0 0 0 4.6200 -1.5539 -0.0888 C 0 0 0 0 0 0 0 0 0 0 0 0 5.9008 -2.0535 -0.1543 C 0 0 0 0 0 0 0 0 0 0 0 0 6.8735 -1.3068 -0.7889 C 0 0 0 0 0 0 0 0 0 0 0 0 8.2748 -1.8375 -0.8688 C 0 0 0 0 0 0 0 0 0 0 0 0 9.0070 -1.3312 0.3809 C 0 0 0 0 0 0 0 0 0 0 0 0 8.9522 0.1220 0.3025 N 0 0 0 0 0 0 0 0 0 0 0 0 6.5937 -0.0825 -1.3535 C 0 0 0 0 0 0 0 0 0 0 0 0 5.3154 0.4255 -1.2929 C 0 0 0 0 0 0 0 0 0 0 0 0 4.8858 2.1063 -2.0566 Br 0 0 0 0 0 0 0 0 0 0 0 0 3.2936 -2.5957 0.7888 Br 0 0 0 0 0 0 0 0 0 0 0 0 -5.5889 1.5133 -1.9832 O 0 0 0 0 0 0 0 0 0 0 0 0 -8.6168 0.7769 -2.2810 Br 0 0 0 0 0 0 0 0 0 0 0 0 -10.3928 -2.1902 -0.1981 H 0 0 0 0 0 0 0 0 0 0 0 0 -10.1954 -0.3690 -0.4670 H 0 0 0 0 0 0 0 0 0 0 0 0 -9.9001 -1.1170 1.1256 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.6818 2.4983 -0.5753 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7994 -0.2945 1.9445 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7229 1.8353 -1.0330 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.6166 0.0687 -0.5242 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.4658 0.1278 -0.6296 H 0 0 0 0 0 0 0 0 0 0 0 0 0.6624 -0.4856 1.2627 H 0 0 0 0 0 0 0 0 0 0 0 0 0.8013 -0.4526 -0.5372 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0279 2.0653 1.2457 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1966 1.9978 -0.5167 H 0 0 0 0 0 0 0 0 0 0 0 0 3.4008 1.8671 0.5899 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9195 0.4020 1.4651 H 0 0 0 0 0 0 0 0 0 0 0 0 6.1814 -3.0138 0.2730 H 0 0 0 0 0 0 0 0 0 0 0 0 8.2555 -2.9370 -0.8898 H 0 0 0 0 0 0 0 0 0 0 0 0 8.7162 -1.4286 -1.7816 H 0 0 0 0 0 0 0 0 0 0 0 0 10.0498 -1.6786 0.3997 H 0 0 0 0 0 0 0 0 0 0 0 0 8.4687 -1.6470 1.2910 H 0 0 0 0 0 0 0 0 0 0 0 0 8.4173 0.5318 1.1097 H 0 0 0 0 0 0 0 0 0 0 0 0 9.9160 0.5295 0.3628 H 0 0 0 0 0 0 0 0 0 0 0 0 7.3426 0.5212 -1.8570 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.4263 0.5507 -2.2370 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 1 0 6 7 1 0 7 8 2 0 8 9 1 0 6 10 1 0 10 11 1 0 11 12 2 0 12 13 1 0 11 14 1 0 14 15 2 0 14 16 1 0 16 17 1 0 17 18 1 0 18 19 1 0 19 20 1 0 20 21 1 0 21 22 2 0 22 23 1 0 23 24 2 0 24 25 1 0 25 26 1 0 26 27 1 0 24 28 1 0 28 29 2 0 29 30 1 0 22 31 1 0 5 32 1 0 4 33 1 0 8 3 1 0 29 21 1 0 6 13 1 1 1 34 1 0 1 35 1 0 1 36 1 0 5 37 1 1 7 38 1 0 10 39 1 0 10 40 1 0 16 41 1 0 17 42 1 0 17 43 1 0 18 44 1 0 18 45 1 0 19 46 1 0 19 47 1 0 23 48 1 0 25 49 1 0 25 50 1 0 26 51 1 0 26 52 1 0 27 53 1 0 27 54 1 0 28 55 1 0 32 56 1 0 M END

Standard InCHIKey	DJOILUOUAWXGIG-PZJWPPBQSA-N
Standard InCHI	InChI=1S/C21H23Br4N3O5/c1-31-18-14(24)9-21(19(29)16(18)25)10-15(28-33-21)20(30)27-5-2-6-32-17-12(22)7-11(3-4-26)8-13(17)23/h7-9,19,29H,2-6,10,26H2,1H3,(H,27,30)/t19-,21+/m0/s1
SMILES	COC1=C([C@@H]([C@@]2(C=C1Br)CC(=NO2)C(=O)NCCCOc1c(cc(CCN)cc1Br)Br)O)Br

Calculated Properties

Physi-Chem Properties

Molecular Weight:	712.84	Volume:	481.723 ? Van der Waals volume.
Dense:	1.48	LogP:	3.057 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.846 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-4.074 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	10.0	Rigid Bonds:	18.0
TPSA:	115.4 ? Topological Polar Surface Area.	H-Bond Acceptor:	8.0
H-Bond Donor:	4.0	Rings:	3.0
Heavy Atoms:	12.0

MedChem Properties

QED Drug-Likeness Score:	0.333	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	4.509	Fsp³:	0.429
MCE-18:	92.4 ? 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:	Accepted
Golden Triangle Rule:	Accepted	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.982	Fluc inhibitor:	0.144 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.028 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.968 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.182	Promiscuous compounds:	0.069

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.053	MDCK Permeability:	-4.829
Pgp-inhibitor:	0.007	Pgp-substrate:	0.751
PAMPA:	0.098 ? 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):	0.007
20% Bioavailability (F20%):	0.002	30% Bioavailability (F30%):	0.046
50% Bioavailability (F50%):	0.706

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.072	MRP1:	1.0
Plasma Protein Binding (PPB):	92.25%	Volume Distribution (VD):	-0.137
Fu:	8.861% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.996
OATP1B3 inhibitor:	0.958	BCRP inhibitor:	0.279
BSEP inhibitor:	0.99

ADMET: Metabolism

CYP1A2-inhibitor:	0.514	CYP1A2-substrate:	0.632
CYP2C19-inhibitor:	0.002	CYP2C19-substrate:	0.914
CYP2C9-inhibitor:	0.028	CYP2C9-substrate:	0.021
CYP2D6-inhibitor:	0.003	CYP2D6-substrate:	0.888
CYP3A4-inhibitor:	0.0	CYP3A4-substrate:	0.966
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.999
HLM stability:	0.005 ? 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):

1.217

Half-life (T1/2):

2.522

ADMET: Toxicity

hERG Blockers:	0.259	hERG Blockers (10um):	0.478
Human Hepatotoxicity (H-HT):	0.63	Drug-induced Liver Injury (DILI):	0.999
AMES Toxicity:	0.962	Rat Oral Acute Toxicity:	0.968
Maximum Recommended Daily Dose:	0.998	Skin Sensitization:	1.0
Carcinogencity:	0.941	Eye Corrosion:	0.002
Eye Irritation:	0.295	Respiratory Toxicity:	0.89
Drug-induced Neurotoxicity:	0.87	Ototoxicity:	0.586
Hematotoxicity:	0.011	Drug-induced Nephrotoxicity:	0.488
Genotoxicity:	1.0	RPMI-8226 Immunitoxicity:	0.172
A549 Cytotoxicity:	0.757	Hek293 Cytotoxicity:	0.853
BCF:	1.701 ? 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:	4.314 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.776 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	5.042 ? 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
NPO32712	suberea ianthelliformis	Species	Aplysinellidae	Eukaryota	n.a.	n.a.	n.a.	PMID[22515429]

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
Inhibition	2

Activity Type	# Activity
Organism	2

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
NPT1548	Organism	Pseudomonas aeruginosa PAO1	Pseudomonas aeruginosa PAO1	Inhibition	=	65.0	%	PMID[17482821]
NPT16	Organism	Staphylococcus aureus	Staphylococcus aureus	Inhibition	=	60.0	%	PMID[22037378]

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 NPC259071 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	16623
0.1-0.2	32862
0.2-0.3	292
0.3-0.4	16
0.4-0.5	17
0.5-0.6	21
0.6-0.7	10
0.7-0.8	0
0.8-0.85	4
0.85-0.9	1
0.9-0.95	0
0.95-1	1

Similarity Score	Similarity Level	Natural Product ID
1.0	High Similarity	NPC77435
0.85	High Similarity	NPC202866
0.8235	Intermediate Similarity	NPC611077
0.8148	Intermediate Similarity	NPC483876
0.8148	Intermediate Similarity	NPC600925
0.8095	Intermediate Similarity	NPC603425
0.7907	Intermediate Similarity	NPC606574
0.7727	Intermediate Similarity	NPC607100
0.7586	Intermediate Similarity	NPC480151
0.7294	Intermediate Similarity	NPC607066
0.7234	Intermediate Similarity	NPC227953
0.7234	Intermediate Similarity	NPC603698
0.6939	Remote Similarity	NPC606635
0.6591	Remote Similarity	NPC487915
0.6526	Remote Similarity	NPC609979
0.6517	Remote Similarity	NPC487914
0.6517	Remote Similarity	NPC489611
0.6517	Remote Similarity	NPC604329
0.6163	Remote Similarity	NPC487872
0.6163	Remote Similarity	NPC608122
0.6105	Remote Similarity	NPC489612
0.6042	Remote Similarity	NPC174607
0.5955	Remote Similarity	NPC487873
0.5897	Remote Similarity	NPC1702
0.5876	Remote Similarity	NPC121571
0.5876	Remote Similarity	NPC8093
0.575	Remote Similarity	NPC158672
0.5714	Remote Similarity	NPC147847
0.5542	Remote Similarity	NPC487917
0.5402	Remote Similarity	NPC473262
0.5402	Remote Similarity	NPC202166
0.5281	Remote Similarity	NPC473261
0.5281	Remote Similarity	NPC300912
0.5222	Remote Similarity	NPC313173
0.5217	Remote Similarity	NPC66855
0.5217	Remote Similarity	NPC181086
0.5213	Remote Similarity	NPC608121
0.5125	Remote Similarity	NPC308571
0.5111	Remote Similarity	NPC145149
0.5109	Remote Similarity	NPC470886
0.5109	Remote Similarity	NPC600759
0.5062	Remote Similarity	NPC128877
0.5053	Remote Similarity	NPC477220

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC259071 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	2817
0.1-0.2	6265
0.2-0.3	68
0.3-0.4	0
0.4-0.5	0
0.5-0.6	0
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
		NPD

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