NPASS Compound

Natural Product: NPC518779

Natural Product ID	NPC518779
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	(3R,6R)-3,6-bis(1H-indol-3-ylmethyl)piperazine-2,5-dione
IUPAC Name	(3~{R},6~{R})-3,6-bis(1~{H}-indol-3-ylmethyl)piperazine-2,5-dione
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 48 52 0 0 0 0 0 0 0 0999 V2000 0.9608 -0.4872 1.0057 O 0 0 0 0 0 0 0 0 0 0 0 0 0.5475 -0.3745 -0.1731 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.8447 -0.1105 -0.4346 N 0 0 0 0 0 0 0 0 0 0 0 0 -1.1918 0.7072 -1.5451 C 0 0 2 0 0 0 0 0 0 0 0 0 -2.6014 0.7125 -2.0029 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.6177 1.1474 -1.0352 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.1224 2.4491 -0.8835 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.0085 2.4964 0.1214 N 0 0 0 0 0 0 0 0 0 0 0 0 -5.1114 1.2640 0.6448 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.8874 0.7903 1.6752 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.8536 -0.5265 2.0470 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.0153 -1.3693 1.3562 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2417 -0.9052 0.3321 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.2578 0.4190 -0.0606 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.3477 0.2485 -2.7115 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.6188 0.6235 -3.8821 O 0 0 0 0 0 0 0 0 0 0 0 0 0.7566 -0.6056 -2.5208 N 0 0 0 0 0 0 0 0 0 0 0 0 1.5054 -0.5159 -1.2815 C 0 0 2 0 0 0 0 0 0 0 0 0 2.4661 -1.6685 -1.1277 C 0 0 0 0 0 0 0 0 0 0 0 0 3.2437 -1.4558 0.1154 C 0 0 0 0 0 0 0 0 0 0 0 0 3.1016 -2.1168 1.3198 C 0 0 0 0 0 0 0 0 0 0 0 0 4.0043 -1.6344 2.1922 N 0 0 0 0 0 0 0 0 0 0 0 0 4.7532 -0.6741 1.6315 C 0 0 0 0 0 0 0 0 0 0 0 0 5.7877 0.1175 2.0825 C 0 0 0 0 0 0 0 0 0 0 0 0 6.3822 1.0483 1.2480 C 0 0 0 0 0 0 0 0 0 0 0 0 5.9087 1.1581 -0.0428 C 0 0 0 0 0 0 0 0 0 0 0 0 4.8641 0.3578 -0.4949 C 0 0 0 0 0 0 0 0 0 0 0 0 4.2810 -0.5592 0.3327 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4880 -0.5522 0.2400 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.8554 1.7546 -1.2815 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.6217 1.3729 -2.9261 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.8415 -0.3035 -2.4139 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.8488 3.3092 -1.4806 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.5473 3.3293 0.4706 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.5585 1.4534 2.2354 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.4670 -0.9247 2.8682 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.9637 -2.4336 1.6281 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.5745 -1.5676 -0.2283 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0639 -1.3043 -3.2341 H 0 0 0 0 0 0 0 0 0 0 0 0 2.0755 0.4360 -1.3348 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9389 -2.6441 -1.1090 H 0 0 0 0 0 0 0 0 0 0 0 0 3.1738 -1.6226 -1.9769 H 0 0 0 0 0 0 0 0 0 0 0 0 2.3710 -2.9010 1.5177 H 0 0 0 0 0 0 0 0 0 0 0 0 4.0878 -1.9815 3.1723 H 0 0 0 0 0 0 0 0 0 0 0 0 6.1625 0.0365 3.0926 H 0 0 0 0 0 0 0 0 0 0 0 0 7.2018 1.6767 1.5986 H 0 0 0 0 0 0 0 0 0 0 0 0 6.3447 1.8766 -0.7347 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5038 0.4537 -1.5074 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 2 0 7 8 1 0 8 9 1 0 9 10 2 0 10 11 1 0 11 12 2 0 12 13 1 0 13 14 2 0 4 15 1 0 15 16 2 0 15 17 1 0 17 18 1 0 18 19 1 0 19 20 1 0 20 21 2 0 21 22 1 0 22 23 1 0 23 24 2 0 24 25 1 0 25 26 2 0 26 27 1 0 27 28 2 0 18 2 1 0 28 20 1 0 14 6 1 0 28 23 1 0 14 9 1 0 3 29 1 0 4 30 1 1 5 31 1 0 5 32 1 0 7 33 1 0 8 34 1 0 10 35 1 0 11 36 1 0 12 37 1 0 13 38 1 0 17 39 1 0 18 40 1 6 19 41 1 0 19 42 1 0 21 43 1 0 22 44 1 0 24 45 1 0 25 46 1 0 26 47 1 0 27 48 1 0 M END

Standard InCHIKey	DNHODRZUCGXYKU-WOJBJXKFSA-N
Standard InCHI	InChI=1S/C22H20N4O2/c27-21-19(9-13-11-23-17-7-3-1-5-15(13)17)25-22(28)20(26-21)10-14-12-24-18-8-4-2-6-16(14)18/h1-8,11-12,19-20,23-24H,9-10H2,(H,25,28)(H,26,27)/t19-,20-/m1/s1
SMILES	O=C1N[C@H](CC2=CNC3=CC=CC=C23)C(=O)N[C@@H]1CC1=CNC2=CC=CC=C12

Calculated Properties

Physi-Chem Properties

Molecular Weight:	372.16	Volume:	381.489 ? Van der Waals volume.
Dense:	0.976	LogP:	2.519 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.517 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-3.21 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	4.0	Rigid Bonds:	28.0
TPSA:	89.78 ? Topological Polar Surface Area.	H-Bond Acceptor:	6.0
H-Bond Donor:	4.0	Rings:	5.0
Heavy Atoms:	6.0

MedChem Properties

QED Drug-Likeness Score:	0.443	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	3.094	Fsp³:	0.182
MCE-18:	78.846 ? 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:	0.822	Fluc inhibitor:	0.836 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.195 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.447 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.007	Promiscuous compounds:	0.288

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-5.41	MDCK Permeability:	-4.547
Pgp-inhibitor:	0.916	Pgp-substrate:	0.496
PAMPA:	0.084 ? 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):	0.117
20% Bioavailability (F20%):	0.297	30% Bioavailability (F30%):	0.832
50% Bioavailability (F50%):	0.852

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.724	MRP1:	0.203
Plasma Protein Binding (PPB):	94.733%	Volume Distribution (VD):	-0.542
Fu:	5.924% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.795
OATP1B3 inhibitor:	0.509	BCRP inhibitor:	0.407
BSEP inhibitor:	0.975

ADMET: Metabolism

CYP1A2-inhibitor:	0.0	CYP1A2-substrate:	0.972
CYP2C19-inhibitor:	0.158	CYP2C19-substrate:	0.001
CYP2C9-inhibitor:	0.012	CYP2C9-substrate:	0.0
CYP2D6-inhibitor:	0.514	CYP2D6-substrate:	0.996
CYP3A4-inhibitor:	0.088	CYP3A4-substrate:	0.542
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.007
HLM stability:	0.736 ? 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):

2.149

Half-life (T1/2):

1.767

ADMET: Toxicity

hERG Blockers:	0.053	hERG Blockers (10um):	0.283
Human Hepatotoxicity (H-HT):	0.247	Drug-induced Liver Injury (DILI):	0.057
AMES Toxicity:	0.832	Rat Oral Acute Toxicity:	0.934
Maximum Recommended Daily Dose:	0.974	Skin Sensitization:	0.365
Carcinogencity:	0.394	Eye Corrosion:	0.0
Eye Irritation:	0.066	Respiratory Toxicity:	0.905
Drug-induced Neurotoxicity:	0.995	Ototoxicity:	0.242
Hematotoxicity:	0.018	Drug-induced Nephrotoxicity:	0.274
Genotoxicity:	1.0	RPMI-8226 Immunitoxicity:	0.051
A549 Cytotoxicity:	0.089	Hek293 Cytotoxicity:	0.088
BCF:	1.547 ? 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:	3.771 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.108 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.816 ? 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
NPO44447	Streptomyces KH29	Genus	Streptomycetaceae	Bacteria	n.a.	n.a.	n.a.	Database[COCONUT]

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 NPC518779 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	38315
0.1-0.2	10112
0.2-0.3	910
0.3-0.4	321
0.4-0.5	134
0.5-0.6	52
0.6-0.7	5
0.7-0.8	0
0.8-0.85	3
0.85-0.9	1
0.9-0.95	0
0.95-1	0

Similarity Score	Similarity Level	Natural Product ID
0.8913	High Similarity	NPC602670
0.82	Intermediate Similarity	NPC606619
0.82	Intermediate Similarity	NPC610347
0.8039	Intermediate Similarity	NPC474561
0.7736	Intermediate Similarity	NPC603509
0.7736	Intermediate Similarity	NPC605537
0.6949	Remote Similarity	NPC600670
0.6119	Remote Similarity	NPC601302
0.6119	Remote Similarity	NPC604280
0.6119	Remote Similarity	NPC610128
0.6029	Remote Similarity	NPC605408
0.5942	Remote Similarity	NPC602956
0.5918	Remote Similarity	NPC310665
0.5909	Remote Similarity	NPC601214
0.5857	Remote Similarity	NPC600013
0.5857	Remote Similarity	NPC601387
0.5857	Remote Similarity	NPC604088
0.5857	Remote Similarity	NPC605600
0.5745	Remote Similarity	NPC279081
0.5741	Remote Similarity	NPC608269
0.5738	Remote Similarity	NPC602245
0.5738	Remote Similarity	NPC606412
0.5694	Remote Similarity	NPC601763
0.5616	Remote Similarity	NPC610080
0.5577	Remote Similarity	NPC55772
0.5577	Remote Similarity	NPC59269
0.5577	Remote Similarity	NPC600736
0.5532	Remote Similarity	NPC96102
0.5472	Remote Similarity	NPC149155
0.5472	Remote Similarity	NPC203468
0.5472	Remote Similarity	NPC190296
0.5472	Remote Similarity	NPC110500
0.5472	Remote Similarity	NPC605329
0.5455	Remote Similarity	NPC200214
0.5417	Remote Similarity	NPC230869
0.5397	Remote Similarity	NPC606618
0.5385	Remote Similarity	NPC78020
0.5345	Remote Similarity	NPC476460
0.5333	Remote Similarity	NPC611116
0.5325	Remote Similarity	NPC326845
0.5325	Remote Similarity	NPC603279
0.5323	Remote Similarity	NPC470497
0.5306	Remote Similarity	NPC29886
0.5294	Remote Similarity	NPC605863
0.5283	Remote Similarity	NPC315555
0.5273	Remote Similarity	NPC248041
0.5254	Remote Similarity	NPC469760
0.5254	Remote Similarity	NPC469786
0.5246	Remote Similarity	NPC603162
0.5238	Remote Similarity	NPC600060
0.52	Remote Similarity	NPC84911
0.519	Remote Similarity	NPC600277
0.5167	Remote Similarity	NPC605381
0.5125	Remote Similarity	NPC603138
0.5106	Remote Similarity	NPC300149
0.5106	Remote Similarity	NPC42372
0.5098	Remote Similarity	NPC73767
0.5091	Remote Similarity	NPC480551
0.5091	Remote Similarity	NPC489200
0.5091	Remote Similarity	NPC480318
0.5088	Remote Similarity	NPC282231
0.5088	Remote Similarity	NPC267885
0.5082	Remote Similarity	NPC602969

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC518779 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	5553
0.1-0.2	3419
0.2-0.3	123
0.3-0.4	42
0.4-0.5	9
0.5-0.6	3
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
0.5532	Remote Similarity	NPD198	Clinical (unspecified phase)
0.5472	Remote Similarity	NPD482	Phase 4
0.5091	Remote Similarity	NPD749	Clinical (unspecified phase)

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