NPASS Compound

Natural Product: NPC577821

Natural Product ID	NPC577821
Common Name ? The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.	methyl (1~{R},15~{S},20~{S})-6,7-dimethoxy-16-methylene-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,10}.0^{4,9}.0^{15,20}]henicosa-2(10),4,6,8,18-pentaene-19-carboxylate
IUPAC Name	methyl (1~{R},15~{S},20~{S})-6,7-dimethoxy-16-methylene-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,10}.0^{4,9}.0^{15,20}]henicosa-2(10),4,6,8,18-pentaene-19-carboxylate
Synonyms
Synthetic Gene Cluster	n.a.
ChEMBL Identifier	n.a.
PubChem CID	n.a.
Chemical Classification	CHEMONTID:0000000 [Organic compounds] [CHEMONTID:0000279] Alkaloids and derivatives [CHEMONTID:0001786] Yohimbine alkaloids

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 60 0 0 0 0 0 0 0 0999 V2000 -3.3425 -2.1110 2.6554 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.9170 -1.6236 1.5651 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.1262 -0.9054 1.6593 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.3343 0.0619 0.6853 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.4858 0.3352 -0.2942 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.8353 1.3801 -1.2486 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.9236 1.9818 -1.1095 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.9990 1.7065 -2.2807 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.2840 2.7149 -3.2424 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.1988 -0.4010 -0.4393 C 0 0 1 0 0 0 0 0 0 0 0 0 -2.0308 0.2765 0.1788 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.9537 -0.6158 0.6550 C 0 0 2 0 0 0 0 0 0 0 0 0 0.3962 -0.0048 0.3793 C 0 0 0 0 0 0 0 0 0 0 0 0 1.4870 -0.7795 0.7021 C 0 0 0 0 0 0 0 0 0 0 0 0 1.2144 -2.1179 1.2804 C 0 0 0 0 0 0 0 0 0 0 0 0 0.0722 -2.7779 0.5877 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.9352 -1.9129 0.0752 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.1814 -2.6245 0.0594 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.3901 -1.7652 0.1940 C 0 0 1 0 0 0 0 0 0 0 0 0 2.6556 -0.1134 0.4044 C 0 0 0 0 0 0 0 0 0 0 0 0 4.0017 -0.3952 0.5127 C 0 0 0 0 0 0 0 0 0 0 0 0 4.9698 0.5262 0.1071 C 0 0 0 0 0 0 0 0 0 0 0 0 6.3165 0.2443 0.2155 O 0 0 0 0 0 0 0 0 0 0 0 0 6.8406 -0.9457 0.7223 C 0 0 0 0 0 0 0 0 0 0 0 0 4.5505 1.7341 -0.4084 C 0 0 0 0 0 0 0 0 0 0 0 0 5.5295 2.6386 -0.8069 O 0 0 0 0 0 0 0 0 0 0 0 0 5.0866 3.8906 -1.3411 C 0 0 0 0 0 0 0 0 0 0 0 0 3.1947 2.0155 -0.5165 C 0 0 0 0 0 0 0 0 0 0 0 0 2.2309 1.1134 -0.1192 C 0 0 0 0 0 0 0 0 0 0 0 0 0.8706 1.1325 -0.1145 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.4307 -2.6658 2.6893 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.8203 -1.9490 3.6358 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.2749 0.6241 0.7552 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.5398 2.3045 -4.2228 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.3830 3.3646 -3.2758 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.1268 3.3326 -2.8827 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9932 -0.5512 -1.5159 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4109 0.8958 1.0424 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.6348 1.0348 -0.5459 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9902 -0.6966 1.7701 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0206 -2.0498 2.3671 H 0 0 0 0 0 0 0 0 0 0 0 0 2.1115 -2.7904 1.1590 H 0 0 0 0 0 0 0 0 0 0 0 0 0.4467 -3.3999 -0.2773 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.3437 -3.5488 1.3017 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.1897 -3.2091 -0.9140 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.1543 -3.3999 0.8479 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.2106 -2.2566 -0.4043 H 0 0 0 0 0 0 0 0 0 0 0 0 4.2799 -1.3411 0.9169 H 0 0 0 0 0 0 0 0 0 0 0 0 7.8969 -1.0544 0.3708 H 0 0 0 0 0 0 0 0 0 0 0 0 6.8858 -0.9746 1.8308 H 0 0 0 0 0 0 0 0 0 0 0 0 6.2983 -1.8548 0.3539 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5103 4.4087 -0.5476 H 0 0 0 0 0 0 0 0 0 0 0 0 4.4233 3.7082 -2.2113 H 0 0 0 0 0 0 0 0 0 0 0 0 5.9675 4.5115 -1.5853 H 0 0 0 0 0 0 0 0 0 0 0 0 2.9168 2.9747 -0.9264 H 0 0 0 0 0 0 0 0 0 0 0 0 0.2664 1.9245 -0.4493 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 2 0 5 6 1 0 6 7 2 0 6 8 1 0 8 9 1 0 5 10 1 0 10 11 1 0 11 12 1 0 12 13 1 0 13 14 2 0 14 15 1 0 15 16 1 0 16 17 1 0 17 18 1 0 18 19 1 0 14 20 1 0 20 21 2 0 21 22 1 0 22 23 1 0 23 24 1 0 22 25 2 0 25 26 1 0 26 27 1 0 25 28 1 0 28 29 2 0 29 30 1 0 19 2 1 0 29 20 1 0 19 10 1 0 17 12 1 0 30 13 1 0 1 31 1 0 1 32 1 0 4 33 1 0 9 34 1 0 9 35 1 0 9 36 1 0 10 37 1 6 11 38 1 0 11 39 1 0 12 40 1 1 15 41 1 0 15 42 1 0 16 43 1 0 16 44 1 0 18 45 1 0 18 46 1 0 19 47 1 6 21 48 1 0 24 49 1 0 24 50 1 0 24 51 1 0 27 52 1 0 27 53 1 0 27 54 1 0 28 55 1 0 30 56 1 0 M END

Standard InCHIKey	RMQMNQMSKODSEY-URLQWDBASA-N
Standard InCHI	InChI=1S/C23H26N2O5/c1-12-16-10-25-6-5-13-15-8-20(27-2)21(28-3)9-18(15)24-22(13)19(25)7-14(16)17(11-30-12)23(26)29-4/h8-9,11,14,16,19,24H,1,5-7,10H2,2-4H3/t14-,16-,19+/m0/s1
SMILES	C=C1OC=C(C(=O)OC)[C@H]2C[C@@H]3C4=C(CCN3C[C@@H]12)C1=CC(OC)=C(OC)C=C1N4

Calculated Properties

Physi-Chem Properties

Molecular Weight:	410.18	Volume:	411.071 ? Van der Waals volume.
Dense:	0.998	LogP:	2.41 ? The logarithm of the n-octanol/water distribution coefficients.
logD7.4:	2.424 ? The logarithm of the n-octanol/water distribution coefficient at pH=7.4.	LogS:	-3.515 ? The logarithm of aqueous solubility value.
Rotatable Bonds:	4.0	Rigid Bonds:	27.0
TPSA:	73.02 ? Topological Polar Surface Area.	H-Bond Acceptor:	7.0
H-Bond Donor:	1.0	Rings:	5.0
Heavy Atoms:	7.0

MedChem Properties

QED Drug-Likeness Score:	0.783	GASA:	1.0 ? GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:	4.097	Fsp³:	0.435
MCE-18:	95.879 ? 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:	0.124	Fluc inhibitor:	0.016 ? The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:	0.882 ? The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1	Green fluorescence:	0.758 ? The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:	0.002	Promiscuous compounds:	0.894

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:	-4.915	MDCK Permeability:	-4.831
Pgp-inhibitor:	0.551	Pgp-substrate:	0.913
PAMPA:	0.001 ? 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%):	0.461	30% Bioavailability (F30%):	0.34
50% Bioavailability (F50%):	0.973

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):	0.074	MRP1:	0.999
Plasma Protein Binding (PPB):	86.291%	Volume Distribution (VD):	0.45
Fu:	12.664% ? The fraction unbound in plasms.	OATP1B1 inhibitor:	0.887
OATP1B3 inhibitor:	0.944	BCRP inhibitor:	0.998
BSEP inhibitor:	0.998

ADMET: Metabolism

CYP1A2-inhibitor:	0.998	CYP1A2-substrate:	0.13
CYP2C19-inhibitor:	0.916	CYP2C19-substrate:	0.198
CYP2C9-inhibitor:	0.0	CYP2C9-substrate:	0.049
CYP2D6-inhibitor:	0.029	CYP2D6-substrate:	0.719
CYP3A4-inhibitor:	1.0	CYP3A4-substrate:	1.0
CYP2B6-substrate:	0.0	CYP2C8-inhibitor:	0.966
HLM stability:	0.022 ? 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):

8.816

Half-life (T1/2):

1.9

ADMET: Toxicity

hERG Blockers:	0.542	hERG Blockers (10um):	0.62
Human Hepatotoxicity (H-HT):	0.579	Drug-induced Liver Injury (DILI):	0.663
AMES Toxicity:	0.558	Rat Oral Acute Toxicity:	0.8
Maximum Recommended Daily Dose:	0.982	Skin Sensitization:	0.848
Carcinogencity:	0.836	Eye Corrosion:	0.0
Eye Irritation:	0.179	Respiratory Toxicity:	0.929
Drug-induced Neurotoxicity:	0.846	Ototoxicity:	0.4
Hematotoxicity:	0.218	Drug-induced Nephrotoxicity:	0.86
Genotoxicity:	0.943	RPMI-8226 Immunitoxicity:	0.11
A549 Cytotoxicity:	0.361	Hek293 Cytotoxicity:	0.49
BCF:	1.105 ? 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:	3.786 ? 48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:	5.509 ? 48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].	LC50FM:	4.741 ? 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
NPO45135	Rauvolfia grandiflora	Species	Apocynaceae	Eukaryota	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 NPC577821 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	22117
0.1-0.2	27049
0.2-0.3	608
0.3-0.4	42
0.4-0.5	22
0.5-0.6	20
0.6-0.7	1
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
0.6067	Remote Similarity	NPC21638
0.5955	Remote Similarity	NPC603895
0.5795	Remote Similarity	NPC131260
0.5747	Remote Similarity	NPC273374
0.5618	Remote Similarity	NPC100898
0.5618	Remote Similarity	NPC148183
0.5618	Remote Similarity	NPC21084
0.5618	Remote Similarity	NPC152768
0.5618	Remote Similarity	NPC605270
0.5568	Remote Similarity	NPC486449
0.5568	Remote Similarity	NPC63199
0.5568	Remote Similarity	NPC111602
0.5568	Remote Similarity	NPC102338
0.5568	Remote Similarity	NPC196251
0.5385	Remote Similarity	NPC312870
0.5385	Remote Similarity	NPC199851
0.5385	Remote Similarity	NPC294909
0.5385	Remote Similarity	NPC254240
0.5385	Remote Similarity	NPC128265
0.5385	Remote Similarity	NPC604675
0.5326	Remote Similarity	NPC293861

Similar Clinical/Approved Drugs

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

● The left chart: Distribution of similarity level between NPC577821 and all drugs/candidates.
● The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

range	Tanimoto Coefficient
0-0.1	4312
0.1-0.2	4741
0.2-0.3	87
0.3-0.4	2
0.4-0.5	6
0.5-0.6	2
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
0.5385	Remote Similarity	NPD4500	Approved
0.5385	Remote Similarity	NPD4501	Approved

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