NPASS Compound

Natural Product: NPC548359

Natural Product ID	NPC548359
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	Methyl (2r)-4-(1h-indol-3-yl)-2-methylbutanoate
IUPAC Name	methyl (2~{R})-4-(1~{H}-indol-3-yl)-2-methyl-butanoate
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 34 35 0 0 0 0 0 0 0 0999 V2000 -4.3842 1.1743 2.1422 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.5477 0.4000 1.2871 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.4513 0.9236 0.6415 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.1860 2.1386 0.8226 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.5579 0.1433 -0.2586 C 0 0 2 0 0 0 0 0 0 0 0 0 -2.3601 -0.4143 -1.4388 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.9208 -1.0143 0.4356 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.0232 -1.7370 -0.5443 C 0 0 0 0 0 0 0 0 0 0 0 0 1.0160 -0.7790 -1.0045 C 0 0 0 0 0 0 0 0 0 0 0 0 1.0723 -0.1484 -2.2088 C 0 0 0 0 0 0 0 0 0 0 0 0 2.1790 0.6234 -2.2011 N 0 0 0 0 0 0 0 0 0 0 0 0 2.8147 0.4885 -1.0185 C 0 0 0 0 0 0 0 0 0 0 0 0 3.9576 1.0130 -0.4558 C 0 0 0 0 0 0 0 0 0 0 0 0 4.3439 0.6579 0.8173 C 0 0 0 0 0 0 0 0 0 0 0 0 3.6326 -0.2200 1.5894 C 0 0 0 0 0 0 0 0 0 0 0 0 2.4756 -0.7571 1.0329 C 0 0 0 0 0 0 0 0 0 0 0 0 2.0992 -0.3973 -0.2359 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.9894 0.4457 2.7238 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7941 1.8356 2.8035 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.1097 1.7891 1.5620 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.7985 0.8178 -0.6944 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3931 0.0365 -1.4150 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4816 -1.5023 -1.3680 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9183 -0.1337 -2.4020 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.7217 -1.7506 0.7193 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.3830 -0.7433 1.3555 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4572 -2.6264 -0.0818 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.5596 -2.1227 -1.4320 H 0 0 0 0 0 0 0 0 0 0 0 0 0.3772 -0.2349 -3.0290 H 0 0 0 0 0 0 0 0 0 0 0 0 2.5141 1.2379 -2.9736 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5394 1.7067 -1.0357 H 0 0 0 0 0 0 0 0 0 0 0 0 5.2539 1.0985 1.2166 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9546 -0.4877 2.5926 H 0 0 0 0 0 0 0 0 0 0 0 0 1.8927 -1.4614 1.6337 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 3 5 1 0 5 6 1 0 5 7 1 0 7 8 1 0 8 9 1 0 9 10 2 0 10 11 1 0 11 12 1 0 12 13 2 0 13 14 1 0 14 15 2 0 15 16 1 0 16 17 2 0 17 9 1 0 17 12 1 0 1 18 1 0 1 19 1 0 1 20 1 0 5 21 1 6 6 22 1 0 6 23 1 0 6 24 1 0 7 25 1 0 7 26 1 0 8 27 1 0 8 28 1 0 10 29 1 0 11 30 1 0 13 31 1 0 14 32 1 0 15 33 1 0 16 34 1 0 M END

Standard InCHIKey	OSINFMIOMWBGDS-SNVBAGLBSA-N
Standard InCHI	InChI=1S/C14H17NO2/c1-10(14(16)17-2)7-8-11-9-15-13-6-4-3-5-12(11)13/h3-6,9-10,15H,7-8H2,1-2H3/t10-/m1/s1
SMILES	COC(=O)[C@H](C)CCC1=CNC2=CC=CC=C12

Calculated Properties

Physi-Chem Properties

Molecular Weight:	231.13	Volume:	248.982 ? Van der Waals volume.
Dense:	0.928	LogP:	3.089 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.942 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-3.41 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	5.0	Rigid Bonds:	11.0
TPSA:	42.09 ? Topological Polar Surface Area.	H-Bond Acceptor:	3.0
H-Bond Donor:	1.0	Rings:	2.0
Heavy Atoms:	3.0

MedChem Properties

QED Drug-Likeness Score:	0.822	GASA:	0.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	2.452	Fsp³:	0.357
MCE-18:	22.0 ? MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.	Lipinski Rule-of-5:	Rejected
Pfizer Rule:	Accepted	GSK Rule:	Rejected
Golden Triangle Rule:	Rejected	BMS Rule:	0
Chelating Alert:	0	PAINS Alert:	0
Colloidal aggregators:	0.047	Fluc inhibitor:	0.174 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.103 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.225 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.073	Promiscuous compounds:	0.64

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.834	MDCK Permeability:	-4.376
Pgp-inhibitor:	0.839	Pgp-substrate:	0.324
PAMPA:	0.068 ? 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):	0.009
20% Bioavailability (F20%):	0.256	30% Bioavailability (F30%):	0.739
50% Bioavailability (F50%):	0.844

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.29	MRP1:	0.756
Plasma Protein Binding (PPB):	83.042%	Volume Distribution (VD):	0.194
Fu:	18.639% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.905
OATP1B3 inhibitor:	0.898	BCRP inhibitor:	0.687
BSEP inhibitor:	0.987

ADMET: Metabolism

CYP1A2-inhibitor:	0.048	CYP1A2-substrate:	0.998
CYP2C19-inhibitor:	0.013	CYP2C19-substrate:	0.928
CYP2C9-inhibitor:	0.005	CYP2C9-substrate:	0.011
CYP2D6-inhibitor:	0.346	CYP2D6-substrate:	0.754
CYP3A4-inhibitor:	0.999	CYP3A4-substrate:	1.0
CYP2B6-substrate:	0.065	CYP2C8-inhibitor:	1.0
HLM stability:	0.935 ? 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):

7.707

Half-life (T1/2):

0.356

ADMET: Toxicity

hERG Blockers:	0.209	hERG Blockers (10um):	0.545
Human Hepatotoxicity (H-HT):	0.713	Drug-induced Liver Injury (DILI):	0.587
AMES Toxicity:	0.58	Rat Oral Acute Toxicity:	0.498
Maximum Recommended Daily Dose:	0.663	Skin Sensitization:	0.705
Carcinogencity:	0.571	Eye Corrosion:	0.103
Eye Irritation:	0.872	Respiratory Toxicity:	0.736
Drug-induced Neurotoxicity:	0.784	Ototoxicity:	0.456
Hematotoxicity:	0.447	Drug-induced Nephrotoxicity:	0.566
Genotoxicity:	0.393	RPMI-8226 Immunitoxicity:	0.063
A549 Cytotoxicity:	0.158	Hek293 Cytotoxicity:	0.235
BCF:	0.888 ? 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:	3.5 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	4.969 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.431 ? 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
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	leaf	n.a.	PMID[24354205]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	twig	n.a.	PMID[24354205]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[34964904]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	PMID[36529712]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	Database[COCONUT]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	Database[HerDing]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCMID]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TCM_Taiwan]
NPO2715	Murraya paniculata	Species	Rutaceae	Eukaryota	n.a.	n.a.	n.a.	Database[TM-MC]
NPO2715	Murraya paniculata	Species	Rutaceae	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

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 NPC548359 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	17889
0.1-0.2	30155
0.2-0.3	1266
0.3-0.4	400
0.4-0.5	124
0.5-0.6	16
0.6-0.7	2
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	Natural Product ID
1.0	High Similarity	NPC200214
0.7143	Intermediate Similarity	NPC600736
0.6531	Remote Similarity	NPC310665
0.6038	Remote Similarity	NPC605329
0.5636	Remote Similarity	NPC480551
0.5614	Remote Similarity	NPC480550
0.5614	Remote Similarity	NPC480549
0.5593	Remote Similarity	NPC480548
0.5532	Remote Similarity	NPC601214
0.5439	Remote Similarity	NPC469358
0.54	Remote Similarity	NPC138370
0.54	Remote Similarity	NPC279081
0.5357	Remote Similarity	NPC489200
0.5323	Remote Similarity	NPC474561
0.5294	Remote Similarity	NPC29886
0.5254	Remote Similarity	NPC602670
0.52	Remote Similarity	NPC96102
0.5172	Remote Similarity	NPC608269
0.5098	Remote Similarity	NPC230869
0.5091	Remote Similarity	NPC78020

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC548359 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	3426
0.1-0.2	5494
0.2-0.3	159
0.3-0.4	56
0.4-0.5	12
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
0.5714	Remote Similarity	NPD1722	Phase 4
0.5283	Remote Similarity	NPD786	Pre-clinical
0.52	Remote Similarity	NPD198	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