NPASS Compound

Natural Product: NPC257240

Natural Product ID	NPC257240
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Ingenol Mebutate
IUPAC Name	n.a.
Synonyms	Ingenol Mebutate; PEP-005; Picato
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	CHEMBL1863513
PubChem CID	6918670
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000012] Lipids and lipid-like molecules [CHEMONTID:0000259] Prenol lipids [CHEMONTID:0001551] Diterpenoids [CHEMONTID:0002875] Tigliane and ingenane diterpenoids

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 65 68 0 0 0 0 0 0 0 0999 V2000 6.2024 1.8460 0.2655 C 0 0 0 0 0 0 0 0 0 0 0 0 5.6652 1.1696 1.4730 C 0 0 0 0 0 0 0 0 0 0 0 0 4.5091 0.5375 1.4591 C 0 0 0 0 0 0 0 0 0 0 0 0 4.0176 -0.1228 2.6952 C 0 0 0 0 0 0 0 0 0 0 0 0 3.6868 0.4607 0.2673 C 0 0 0 0 0 0 0 0 0 0 0 0 4.1105 1.0208 -0.7689 O 0 0 0 0 0 0 0 0 0 0 0 0 2.4678 -0.1927 0.2109 O 0 0 0 0 0 0 0 0 0 0 0 0 1.7086 -0.2369 -0.9743 C 0 0 1 0 0 0 0 0 0 0 0 0 1.5387 -1.5881 -1.5164 C 0 0 0 0 0 0 0 0 0 0 0 0 0.3106 -1.9864 -1.3034 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.4366 -0.9558 -0.6136 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.6536 -1.3111 0.8360 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.1488 -2.7372 1.0434 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.9916 -1.0803 1.4257 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.2511 -1.2901 0.7294 C 0 0 2 0 0 0 0 0 0 0 0 0 -3.7747 -0.1361 -0.1762 C 0 0 2 0 0 0 0 0 0 0 0 0 -2.5589 0.5095 -0.5583 C 0 0 2 0 0 0 0 0 0 0 0 0 -2.4162 1.5023 -1.5893 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.2491 1.8113 -2.1371 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.2783 3.0369 -2.9799 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.9047 2.6785 -4.2689 O 0 0 0 0 0 0 0 0 0 0 0 0 0.0359 1.1204 -2.0290 C 0 0 2 0 0 0 0 0 0 0 0 0 0.3256 0.3511 -0.8036 C 0 0 2 0 0 0 0 0 0 0 0 0 0.3305 1.1074 0.3579 O 0 0 0 0 0 0 0 0 0 0 0 0 1.0400 2.1111 -2.1257 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.7790 -0.6838 -1.1131 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.3460 -1.3213 -1.9381 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.3819 -0.3071 1.1391 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.0830 0.6350 2.2857 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.7518 -0.9435 1.2337 C 0 0 0 0 0 0 0 0 0 0 0 0 2.6225 -2.3837 -2.2109 C 0 0 0 0 0 0 0 0 0 0 0 0 5.5779 2.6922 -0.0757 H 0 0 0 0 0 0 0 0 0 0 0 0 7.1926 2.2988 0.5138 H 0 0 0 0 0 0 0 0 0 0 0 0 6.4265 1.1028 -0.5314 H 0 0 0 0 0 0 0 0 0 0 0 0 6.2407 1.1922 2.4063 H 0 0 0 0 0 0 0 0 0 0 0 0 4.8277 -0.7391 3.1782 H 0 0 0 0 0 0 0 0 0 0 0 0 3.1817 -0.7989 2.5247 H 0 0 0 0 0 0 0 0 0 0 0 0 3.7114 0.6069 3.4758 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2769 0.3294 -1.7775 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.1377 -2.9513 -1.5863 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0825 -0.6853 1.3929 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.4287 -2.9910 2.1043 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5760 -3.4491 0.3429 H 0 0 0 0 0 0 0 0 0 0 0 0 0.9755 -2.7511 1.0442 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.0415 -1.8497 2.2774 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9915 -0.1356 2.0573 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.5815 -2.3122 0.4466 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.4025 -0.5039 -1.0395 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.0928 0.9332 0.3584 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.2902 2.0135 -1.9289 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.4628 3.7026 -2.5731 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2503 3.5520 -2.9333 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5000 1.9783 -4.5953 H 0 0 0 0 0 0 0 0 0 0 0 0 0.2397 0.4464 -2.9084 H 0 0 0 0 0 0 0 0 0 0 0 0 1.1968 1.6071 0.4650 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0822 2.6231 -1.2997 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.0120 1.1269 2.5593 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3446 1.4103 2.0107 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7508 0.0143 3.1428 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.7052 -2.0475 1.1519 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.4081 -0.5919 0.3999 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.2863 -0.6826 2.1650 H 0 0 0 0 0 0 0 0 0 0 0 0 2.8060 -2.0060 -3.2187 H 0 0 0 0 0 0 0 0 0 0 0 0 2.3462 -3.4488 -2.2350 H 0 0 0 0 0 0 0 0 0 0 0 0 3.5316 -2.3070 -1.5768 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 9 10 2 0 11 10 1 6 11 12 1 0 12 13 1 0 12 14 1 0 14 15 1 0 15 16 1 0 16 17 1 0 17 18 1 0 18 19 2 0 19 20 1 0 20 21 1 0 19 22 1 0 22 23 1 0 23 24 1 1 22 25 1 0 17 26 1 0 26 27 2 0 16 28 1 0 28 29 1 0 28 30 1 0 9 31 1 0 23 8 1 0 26 11 1 0 23 11 1 0 28 15 1 0 1 32 1 0 1 33 1 0 1 34 1 0 2 35 1 0 4 36 1 0 4 37 1 0 4 38 1 0 8 39 1 6 10 40 1 0 12 41 1 1 13 42 1 0 13 43 1 0 13 44 1 0 14 45 1 0 14 46 1 0 15 47 1 6 16 48 1 6 17 49 1 1 18 50 1 0 20 51 1 0 20 52 1 0 21 53 1 0 22 54 1 6 24 55 1 0 25 56 1 0 29 57 1 0 29 58 1 0 29 59 1 0 30 60 1 0 30 61 1 0 30 62 1 0 31 63 1 0 31 64 1 0 31 65 1 0 M END

Standard InCHIKey	VDJHFHXMUKFKET-WDUFCVPESA-N
Standard InCHI	InChI=1S/C25H34O6/c1-7-12(2)22(29)31-21-13(3)10-24-14(4)8-17-18(23(17,5)6)16(20(24)28)9-15(11-26)19(27)25(21,24)30/h7,9-10,14,16-19,21,26-27,30H,8,11H2,1-6H3/b12-7-/t14-,16+,17-,18+,19-,21+,24+,25+/m1/s1
SMILES	C/C=C(/C)C(=O)O[C@H]1C(=C[C@]23[C@H](C)C[C@@H]4[C@H]([C@H](C=C(CO)[C@H]([C@]13O)O)C2=O)C4(C)C)C

Calculated Properties

Physi-Chem Properties

MedChem Properties

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

ADMET: Distribution

ADMET: Metabolism

ADMET: Excretion

ADMET: Toxicity

Species Source

Organism ID	Organism Name	Taxonomy Level	Family	SuperKingdom	Isolation Part	Collection Location	Collection Time	Reference
NPO13882	Euphorbia grandicornis	Species	Euphorbiaceae	Eukaryota	n.a.	aerial part	n.a.	PMID[21319774]
NPO13882	Euphorbia grandicornis	Species	Euphorbiaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[27731641]
NPO41583	Xylaria flabelliformis + Aspergillus fischeri	Species	n.a.	n.a.	n.a.	n.a.	n.a.	PMID[32096649]
NPO1853	Euphorbia canariensis	Species	Euphorbiaceae	Eukaryota	n.a.	n.a.	n.a.	Database[UNPD]
NPO13882	Euphorbia grandicornis	Species	Euphorbiaceae	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
EC50	15
Inhibition	10
FC	1
Hit score	1
Ratio CC50/EC50	3
CC50	2

Activity Type	# Activity
Cell line	2
Individual protein	5
Protein family	1
Organism	12
Single protein	2
Others	9
Non-molecular	1

Molecular-level activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT20556	Single protein	Replicase polyprotein 1ab	Severe acute respiratory syndrome coronavirus 2	Inhibition	=	10.71	%	DOI[10.6019/CHEMBL4495564]
NPT20556	Single protein	Replicase polyprotein 1ab	Severe acute respiratory syndrome coronavirus 2	Inhibition	=	-0.1615	%	DOI[10.6019/CHEMBL4495564]
NPT692	Individual protein	Histone deacetylase 6	Homo sapiens	Inhibition	=	0.27	%	HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators
NPT692	Individual protein	Histone deacetylase 6	Homo sapiens	Inhibition	=	9.71	%	HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators
NPT881	Individual protein	Protein kinase C delta	Homo sapiens	EC50	=	4.1	nM	PMID[24332494]
NPT316	Protein family	Protein kinase C (PKC)	Homo sapiens	EC50	=	72.5	nM	PMID[27731641]

In vitro activity

Target ID	Target Type	Target Name	Target Organism	Activity Type	Activity Relation	Value	Unit	Reference
NPT466	Cell line	U-937	Homo sapiens	CC50	>	200.0	nM	PMID[29541372]
NPT25	Cell line	MT4	Homo sapiens	CC50	>	9300.0	nM	PMID[30031972]
NPT20555	Organism	SARS-CoV-2	Severe acute respiratory syndrome coronavirus 2	Inhibition	=	1.08	%	DOI[10.21203/rs.3.rs-23951/v1]
NPT20555	Organism	SARS-CoV-2	Severe acute respiratory syndrome coronavirus 2	Hit score	=	0.3195	n.a.	DOI[10.1101/2020.04.21.054387]
NPT20555	Organism	SARS-CoV-2	Severe acute respiratory syndrome coronavirus 2	Inhibition	=	2.17	%	DOI[10.6019/CHEMBL4495565]
NPT20555	Organism	SARS-CoV-2	Severe acute respiratory syndrome coronavirus 2	Inhibition	=	1.7	%	DOI[10.6019/CHEMBL4495565]
NPT20529	Non-molecular	NON-PROTEIN TARGET	n.a.	EC50	=	22900.0	nM	PMID[25970561]
NPT332	Organism	Human immunodeficiency virus type 2 (ISOLATE ROD)	Human immunodeficiency virus type 2 (ISOLATE ROD)	EC50	=	9.0	nM	PMID[25970561]
NPT24	Organism	Human immunodeficiency virus 1	Human immunodeficiency virus 1	EC50	=	17.0	nM	PMID[25970561]
NPT24	Organism	Human immunodeficiency virus 1	Human immunodeficiency virus 1	FC	=	9.7	n.a.	PMID[29541372]
NPT24	Organism	Human immunodeficiency virus 1	Human immunodeficiency virus 1	EC50	=	4.8	nM	PMID[29541372]
NPT24	Organism	Human immunodeficiency virus 1	Human immunodeficiency virus 1	EC50	=	4.5	nM	PMID[30031972]
NPT24	Organism	Human immunodeficiency virus 1	Human immunodeficiency virus 1	EC50	=	4.2	nM	PMID[30031972]
NPT2	Others	Unspecified	n.a.	EC50	=	10.3	nM	PMID[24332494]
NPT2	Others	Unspecified	n.a.	EC50	=	11.2	nM	PMID[24332494]
NPT2	Others	Unspecified	n.a.	EC50	=	8.7	nM	PMID[24332494]
NPT2	Others	Unspecified	n.a.	Ratio CC50/EC50	=	7847.0	n.a.	PMID[25970561]
NPT2	Others	Unspecified	n.a.	Ratio CC50/EC50	=	2.3	n.a.	PMID[25970561]
NPT2	Others	Unspecified	n.a.	Ratio CC50/EC50	=	13451.0	n.a.	PMID[25970561]

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 NPC257240 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	16949
0.1-0.2	28956
0.2-0.3	3851
0.3-0.4	58
0.4-0.5	18
0.5-0.6	13
0.6-0.7	4
0.7-0.8	0
0.8-0.85	3
0.85-0.9	0
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.8276	Intermediate Similarity	NPC482234
0.8276	Intermediate Similarity	NPC303053
0.8	Intermediate Similarity	NPC607683
0.7869	Intermediate Similarity	NPC308191
0.7869	Intermediate Similarity	NPC38423
0.7273	Intermediate Similarity	NPC482240
0.7273	Intermediate Similarity	NPC482239
0.7059	Intermediate Similarity	NPC46269
0.7059	Intermediate Similarity	NPC106395
0.6716	Remote Similarity	NPC482235
0.6716	Remote Similarity	NPC479252
0.6667	Remote Similarity	NPC600642
0.6338	Remote Similarity	NPC482236
0.5833	Remote Similarity	NPC47951
0.5797	Remote Similarity	NPC267734
0.5797	Remote Similarity	NPC482241
0.5769	Remote Similarity	NPC479253
0.5645	Remote Similarity	NPC261341
0.5541	Remote Similarity	NPC607208
0.5526	Remote Similarity	NPC482242
0.5526	Remote Similarity	NPC482243
0.5455	Remote Similarity	NPC67290
0.5455	Remote Similarity	NPC133677
0.527	Remote Similarity	NPC609657
0.5263	Remote Similarity	NPC138757
0.5256	Remote Similarity	NPC607157

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC257240 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	6549
0.1-0.2	2568
0.2-0.3	32
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	1

Similarity Score	Similarity Level	Drug ID	Developmental Stage
1.0	High Similarity	NPD6371	Phase 4

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