NPASS Compound

Natural Product: NPC8369

Natural Product ID	NPC8369
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Withaphysalin M
IUPAC Name	n.a.
Synonyms	Withaphysalin M
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL450392
PubChem CID	10096775
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000012] Lipids and lipid-like molecules [CHEMONTID:0000258] Steroids and steroid derivatives [CHEMONTID:0001125] Steroid lactones [CHEMONTID:0001560] Withanolides 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 69 75 0 0 0 0 0 0 0 0999 V2000 6.8598 1.4024 0.9625 C 0 0 0 0 0 0 0 0 0 0 0 0 5.8740 0.3644 0.5394 C 0 0 0 0 0 0 0 0 0 0 0 0 6.2950 -0.8112 0.1047 C 0 0 0 0 0 0 0 0 0 0 0 0 7.7746 -1.0272 0.0691 C 0 0 0 0 0 0 0 0 0 0 0 0 5.3821 -1.8667 -0.3560 C 0 0 0 0 0 0 0 0 0 0 0 0 5.8062 -2.9793 -0.7613 O 0 0 0 0 0 0 0 0 0 0 0 0 4.0188 -1.5280 -0.3027 O 0 0 0 0 0 0 0 0 0 0 0 0 3.7406 -0.1464 -0.4461 C 0 0 2 0 0 0 0 0 0 0 0 0 4.4073 0.6061 0.6194 C 0 0 0 0 0 0 0 0 0 0 0 0 2.2902 0.0102 -0.6750 C 0 0 1 0 0 0 0 0 0 0 0 0 2.0303 -0.6490 -2.0435 C 0 0 0 0 0 0 0 0 0 0 0 0 1.3656 -0.4903 0.3833 C 0 0 1 0 0 0 0 0 0 0 0 0 1.5138 0.4591 1.5746 C 0 0 0 0 0 0 0 0 0 0 0 0 0.1248 0.9486 1.9429 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7512 0.1015 1.1429 C 0 0 1 0 0 0 0 0 0 0 0 0 -2.0946 0.5859 0.7853 C 0 0 2 0 0 0 0 0 0 0 0 0 -2.8986 1.1776 1.8990 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2710 1.4595 1.4083 C 0 0 2 0 0 0 0 0 0 0 0 0 -4.7949 0.8400 0.2797 C 0 0 2 0 0 0 0 0 0 0 0 0 -6.2998 0.8624 0.0561 C 0 0 2 0 0 0 0 0 0 0 0 0 -6.9439 -0.3693 0.5629 C 0 0 0 0 0 0 0 0 0 0 0 0 -6.3159 -1.5066 0.3904 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.0246 -1.5194 -0.2843 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.6940 -2.6291 -0.8219 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.1350 -0.3308 -0.3541 C 0 0 1 0 0 0 0 0 0 0 0 0 -3.8349 0.0001 -1.8201 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.8555 -0.6760 0.3364 C 0 0 1 0 0 0 0 0 0 0 0 0 -1.9578 -1.6170 -0.3522 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.7153 -0.9864 -0.9964 C 0 0 0 0 0 0 0 0 0 0 0 0 0.0298 -0.0620 -0.1531 C 0 0 2 0 0 0 0 0 0 0 0 0 0.4027 1.2381 -0.7705 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3210 2.1735 -1.1993 O 0 0 0 0 0 0 0 0 0 0 0 0 1.8141 1.3286 -0.8349 O 0 0 0 0 0 0 0 0 0 0 0 0 -6.6399 1.1240 -1.2592 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.2092 2.0971 0.0675 O 0 0 0 0 0 0 0 0 0 0 0 0 7.1698 2.0196 0.0928 H 0 0 0 0 0 0 0 0 0 0 0 0 6.3674 2.0433 1.7206 H 0 0 0 0 0 0 0 0 0 0 0 0 7.7304 0.9149 1.4313 H 0 0 0 0 0 0 0 0 0 0 0 0 8.0524 -1.9152 -0.5259 H 0 0 0 0 0 0 0 0 0 0 0 0 8.3125 -0.1650 -0.3666 H 0 0 0 0 0 0 0 0 0 0 0 0 8.1034 -1.1079 1.1266 H 0 0 0 0 0 0 0 0 0 0 0 0 4.2415 0.1714 -1.4128 H 0 0 0 0 0 0 0 0 0 0 0 0 4.1544 0.2479 1.6633 H 0 0 0 0 0 0 0 0 0 0 0 0 4.3044 1.7144 0.5491 H 0 0 0 0 0 0 0 0 0 0 0 0 2.8887 -0.2829 -2.6892 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1480 -0.2514 -2.5351 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1508 -1.7294 -2.0093 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4530 -1.5309 0.6473 H 0 0 0 0 0 0 0 0 0 0 0 0 2.0749 1.3675 1.3174 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9216 -0.1235 2.4230 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0698 0.8059 3.0367 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0437 2.0056 1.7308 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.8033 -0.9138 1.5898 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.1557 1.2732 -0.0754 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4237 2.1453 2.1949 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9479 0.5340 2.8003 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.9138 2.0139 2.1184 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.7116 1.7103 0.6608 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.8994 -0.3313 1.0580 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.7404 -2.4455 0.7420 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.4477 -0.8986 -2.3412 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7548 0.2937 -2.3584 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1638 0.8592 -1.8239 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1558 -1.1565 1.3180 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4230 -2.2166 -1.1690 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5355 -2.3916 0.3538 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1415 -0.4289 -1.8832 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.1455 -1.8891 -1.3675 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.5691 2.0736 -1.5008 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 1 0 2 3 2 0 3 4 1 0 3 5 1 0 5 6 2 0 5 7 1 0 7 8 1 0 8 9 1 0 8 10 1 0 10 11 1 6 10 12 1 0 12 13 1 0 13 14 1 0 14 15 1 0 15 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 23 25 1 0 25 26 1 6 25 27 1 0 27 28 1 0 28 29 1 0 30 29 1 6 30 31 1 0 31 32 2 0 31 33 1 0 20 34 1 0 19 35 1 6 9 2 1 0 33 10 1 0 30 12 1 0 30 15 1 0 27 16 1 0 35 18 1 0 25 19 1 0 1 36 1 0 1 37 1 0 1 38 1 0 4 39 1 0 4 40 1 0 4 41 1 0 8 42 1 6 9 43 1 0 9 44 1 0 11 45 1 0 11 46 1 0 11 47 1 0 12 48 1 1 13 49 1 0 13 50 1 0 14 51 1 0 14 52 1 0 15 53 1 1 16 54 1 6 17 55 1 0 17 56 1 0 18 57 1 1 20 58 1 1 21 59 1 0 22 60 1 0 26 61 1 0 26 62 1 0 26 63 1 0 27 64 1 1 28 65 1 0 28 66 1 0 29 67 1 0 29 68 1 0 34 69 1 0 M END

Standard InCHIKey	GUTRJAVJYHGRQZ-BGDMQGTOSA-N
Standard InCHI	InChI=1S/C28H34O7/c1-13-11-21(33-23(31)14(13)2)26(4)18-6-5-17-15-12-22-28(34-22)20(30)8-7-19(29)25(28,3)16(15)9-10-27(17,18)24(32)35-26/h7-8,15-18,20-22,30H,5-6,9-12H2,1-4H3/t15-,16+,17+,18-,20+,21-,22-,25+,26-,27-,28-/m1/s1
SMILES	CC1=C(C)C(=O)O[C@H](C1)[C@@]1(C)[C@H]2CC[C@H]3[C@@H]4C[C@@H]5[C@@]6([C@H](C=CC(=O)[C@]6(C)[C@H]4CC[C@]23C(=O)O1)O)O5

Calculated Properties

Physi-Chem Properties

Molecular Weight:	482.23	Volume:	481.298 ? Van der Waals volume.
Dense:	1.002	LogP:	2.683 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	3.083 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-4.467 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	1.0	Rigid Bonds:	35.0
TPSA:	102.43 ? Topological Polar Surface Area.	H-Bond Acceptor:	7.0
H-Bond Donor:	1.0	Rings:	7.0
Heavy Atoms:	7.0

MedChem Properties

QED Drug-Likeness Score:	0.453	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	6.292	Fsp³:	0.75
MCE-18:	166.224 ? 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:	Rejected	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.763	Fluc inhibitor:	0.072 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.01 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.0 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.175	Promiscuous compounds:	0.48

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.827	MDCK Permeability:	-4.514
Pgp-inhibitor:	0.054	Pgp-substrate:	0.041
PAMPA:	0.64 ? 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%):	0.63	30% Bioavailability (F30%):	0.621
50% Bioavailability (F50%):	0.941

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.802	MRP1:	0.997
Plasma Protein Binding (PPB):	80.072%	Volume Distribution (VD):	-0.114
Fu:	14.598% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.94
OATP1B3 inhibitor:	0.923	BCRP inhibitor:	0.003
BSEP inhibitor:	0.999

ADMET: Metabolism

CYP1A2-inhibitor:	0.999	CYP1A2-substrate:	0.0
CYP2C19-inhibitor:	1.0	CYP2C19-substrate:	0.0
CYP2C9-inhibitor:	0.997	CYP2C9-substrate:	0.0
CYP2D6-inhibitor:	0.023	CYP2D6-substrate:	0.0
CYP3A4-inhibitor:	0.222	CYP3A4-substrate:	0.525
CYP2B6-substrate:	0.006	CYP2C8-inhibitor:	0.995
HLM stability:	0.8 ? 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):

6.095

Half-life (T1/2):

2.193

ADMET: Toxicity

hERG Blockers:	0.039	hERG Blockers (10um):	0.351
Human Hepatotoxicity (H-HT):	0.684	Drug-induced Liver Injury (DILI):	0.475
AMES Toxicity:	0.743	Rat Oral Acute Toxicity:	0.776
Maximum Recommended Daily Dose:	0.884	Skin Sensitization:	0.997
Carcinogencity:	0.954	Eye Corrosion:	0.015
Eye Irritation:	0.498	Respiratory Toxicity:	0.54
Drug-induced Neurotoxicity:	0.428	Ototoxicity:	0.301
Hematotoxicity:	0.147	Drug-induced Nephrotoxicity:	0.898
Genotoxicity:	0.984	RPMI-8226 Immunitoxicity:	0.173
A549 Cytotoxicity:	0.065	Hek293 Cytotoxicity:	0.48
BCF:	1.062 ? 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:	3.882 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.48 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.91 ? 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
NPO10618	Acnistus arborescens	Species	Solanaceae	Eukaryota	leaves	n.a.	n.a.	PMID[15104512]
NPO10618	Acnistus arborescens	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[20590148]
NPO10618	Acnistus arborescens	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO10618	Acnistus arborescens	Species	Solanaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO10618	Acnistus arborescens	Species	Solanaceae	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
IC50	1
ED50	3

Activity Type	# Activity
Cell line	3
Organism	1

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
NPT1034	Cell line	Lu1	Homo sapiens	ED50	=	0.22	ug ml-1	PMID[26034885]
NPT858	Cell line	LNCaP	Homo sapiens	ED50	=	1.0	ug ml-1	PMID[26034885]
NPT83	Cell line	MCF7	Homo sapiens	ED50	=	1.2	ug ml-1	PMID[26034885]
NPT580	Organism	Trypanosoma cruzi	Trypanosoma cruzi	IC50	=	0.7	ug.mL-1	PMID[8388433]

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 NPC8369 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	18601
0.1-0.2	28057
0.2-0.3	3030
0.3-0.4	106
0.4-0.5	23
0.5-0.6	25
0.6-0.7	8
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
0.7333	Intermediate Similarity	NPC42673
0.7051	Intermediate Similarity	NPC473593
0.6883	Remote Similarity	NPC475520
0.6533	Remote Similarity	NPC286528
0.6329	Remote Similarity	NPC474181
0.6282	Remote Similarity	NPC609580
0.6203	Remote Similarity	NPC183580
0.6049	Remote Similarity	NPC67569
0.6	Remote Similarity	NPC88326
0.6	Remote Similarity	NPC474370
0.5926	Remote Similarity	NPC153700
0.5833	Remote Similarity	NPC23786
0.575	Remote Similarity	NPC140055
0.575	Remote Similarity	NPC167606
0.5476	Remote Similarity	NPC312824
0.5476	Remote Similarity	NPC20302
0.5432	Remote Similarity	NPC50774
0.5357	Remote Similarity	NPC8374
0.5349	Remote Similarity	NPC470494
0.5301	Remote Similarity	NPC125794
0.5301	Remote Similarity	NPC171401
0.5301	Remote Similarity	NPC473274
0.5294	Remote Similarity	NPC470492
0.5294	Remote Similarity	NPC264954
0.5238	Remote Similarity	NPC470493
0.5181	Remote Similarity	NPC270929
0.5176	Remote Similarity	NPC329671
0.5119	Remote Similarity	NPC473720
0.5116	Remote Similarity	NPC600975
0.5116	Remote Similarity	NPC602010
0.5116	Remote Similarity	NPC608655
0.5111	Remote Similarity	NPC3381
0.5059	Remote Similarity	NPC470878
0.5057	Remote Similarity	NPC609769
0.5057	Remote Similarity	NPC610140

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC8369 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	6652
0.1-0.2	2346
0.2-0.3	151
0.3-0.4	0
0.4-0.5	0
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
0.575	Remote Similarity	NPD7115	Discovery

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