Natural Product: NPC161774

Natural Product IDNPC161774
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Cyclo(L-Leu-L-Pro)
IUPAC Name (3S,8aS)-3-(2-methylpropyl)-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione
Synonyms
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL508326
PubChem CID 7074739
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000264] Organic acids and derivatives
      • [CHEMONTID:0000265] Carboxylic acids and derivatives
        • [CHEMONTID:0000013] Amino acids, peptides, and analogues
          • [CHEMONTID:0000347] Amino acids and derivatives
            • [CHEMONTID:0000060] Alpha amino acids 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

Standard InCHIKey SZJNCZMRZAUNQT-IUCAKERBSA-N
Standard InCHI InChI=1S/C11H18N2O2/c1-7(2)6-8-11(15)13-5-3-4-9(13)10(14)12-8/h7-9H,3-6H2,1-2H3,(H,12,14)/t8-,9-/m0/s1
SMILES CC(C[C@@H]1N=C(O)[C@H]2N(C1=O)CCC2)C

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   210.14 Volume:   216.0
?
Van der Waals volume.
Dense:   0.973 LogP:   0.658
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   0.807
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   -1.393
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   2.0 Rigid Bonds:   11.0
TPSA:   52.9
?
Topological Polar Surface Area.
 H-Bond Acceptor:   4.0
H-Bond Donor:   1.0 Rings:   2.0
Heavy Atoms:   4.0

MedChem Properties

QED Drug-Likeness Score:   0.748 GASA:   1.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   3.745 Fsp3:   0.818
MCE-18:   30.0
?
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:   0.286 Fluc inhibitor:   0.0
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.019
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.245
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.016 Promiscuous compounds:   0.077

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.833 MDCK Permeability:   -4.576
Pgp-inhibitor:   0.613 Pgp-substrate:   0.898
PAMPA:   0.492
?
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):   0.828
20% Bioavailability (F20%):   0.952 30% Bioavailability (F30%):   0.988
50% Bioavailability (F50%):   0.971

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.02 MRP1:   0.864
Plasma Protein Binding (PPB):   25.776% Volume Distribution (VD):   -0.017
Fu: 67.684%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.725
OATP1B3 inhibitor:   0.571 BCRP inhibitor:   0.539
BSEP inhibitor:   0.402

ADMET: Metabolism

CYP1A2-inhibitor:   0.008 CYP1A2-substrate:   0.003
CYP2C19-inhibitor:   0.875 CYP2C19-substrate:   0.007
CYP2C9-inhibitor:   0.186 CYP2C9-substrate:   0.0
CYP2D6-inhibitor:   0.003 CYP2D6-substrate:   0.005
CYP3A4-inhibitor:   0.965 CYP3A4-substrate:   0.001
CYP2B6-substrate:   0.0 CYP2C8-inhibitor:   0.014
HLM stability:   0.051
?
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):  9.278 Half-life (T1/2):  1.656

ADMET: Toxicity

hERG Blockers:  0.005 hERG Blockers (10um):  0.018
Human Hepatotoxicity (H-HT):  1.0 Drug-induced Liver Injury (DILI):  0.997
AMES Toxicity:  0.194 Rat Oral Acute Toxicity:  0.66
Maximum Recommended Daily Dose:  0.685 Skin Sensitization:  1.0
Carcinogencity:  0.83 Eye Corrosion:  0.0
Eye Irritation:  0.944 Respiratory Toxicity:  0.956
Drug-induced Neurotoxicity:  0.742 Ototoxicity:  0.634
Hematotoxicity:  0.319 Drug-induced Nephrotoxicity:  0.899
Genotoxicity:  1.0 RPMI-8226 Immunitoxicity:  0.004
A549 Cytotoxicity:  0.0 Hek293 Cytotoxicity:  0.017
BCF:   0.405
?
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:   3.096
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   4.46
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   3.748
?
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
NPO42562 Aspergillus versicolor ZBY-3 Genus Aspergillaceae Eukaryota n.a. n.a. n.a. PMID[ 25076061]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. DOI[10.1016/j.carres.2012.01.012]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[10556916]
NPO23507 Fissistigma balansae Species Annonaceae Eukaryota n.a. n.a. n.a. PMID[10978218]
NPO1520 Callyspongia pseudoreticulata Species Callyspongiidae Eukaryota n.a. n.a. n.a. PMID[12828480]
NPO24252 Uvaria hamiltonii Species Annonaceae Eukaryota n.a. n.a. n.a. PMID[14552774]
NPO30995 Achromobacter xylosoxidans Species Alcaligenaceae Bacteria n.a. n.a. n.a. PMID[15574949]
NPO23039 Turbo stenogyrus Species Turbinidae Eukaryota n.a. n.a. n.a. PMID[16038534]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[19406895]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[19917748]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[20932054]
NPO997 Peltodon longipes Species Lamiaceae Eukaryota roots Santa Maria, South Brazil 2007-Dec PMID[21775156]
NPO17376 Bacillus amyloliquefaciens Species Bacillaceae Bacteria n.a. n.a. n.a. PMID[23265519]
NPO17376 Bacillus amyloliquefaciens Species Bacillaceae Bacteria n.a. n.a. n.a. PMID[24698790]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[25043228]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[25960261]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. PMID[26562741]
NPO17376 Bacillus amyloliquefaciens Species Bacillaceae Bacteria n.a. n.a. n.a. PMID[27934031]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. PMID[29517238]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. PMID[31625751]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. PMID[32603106]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. Along the Valencian coast, Spain 2020-Jun&Jul PMID[35161358]
NPO6621 Salvadora persica Species Salvadoraceae Eukaryota n.a. n.a. n.a. PMID[36514376]
NPO6621 Salvadora persica Species Salvadoraceae Eukaryota n.a. n.a. n.a. PMID[36854946]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. Antarctic n.a. PMID[8882433]
NPO24252 Uvaria hamiltonii Species Annonaceae Eukaryota leaf and stem n.a. n.a. PMID[9584399]
NPO2853 Eschweilera coriacea Species Lecythidaceae Eukaryota bark Suriname rainforest n.a. PMID[9677272]
NPO42562 Aspergillus versicolor ZBY-3 Genus Aspergillaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO17376 Bacillus amyloliquefaciens Species Bacillaceae Bacteria n.a. n.a. n.a. Database[COCONUT]
NPO23277 Lobophora papenfussii Species Dictyotaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO23507 Fissistigma balansae Species Annonaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO24252 Uvaria hamiltonii Species Annonaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO23039 Turbo stenogyrus Species Turbinidae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO5665 Ulva pertusa Species Ulvaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO6621 Salvadora persica Species Salvadoraceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO1920 Podocarpus elongata Species Podocarpaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO997 Peltodon longipes Species Lamiaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO3809 Eucalyptus cladocalyx Species Myrtaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO2853 Eschweilera coriacea Species Lecythidaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. Database[COCONUT]
NPO12670 Lactobacillus plantarum Species Lactobacillaceae Bacteria n.a. n.a. n.a. Database[COCONUT]
NPO23741 Aspergillus violaceus Species Aspergillaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. Database[FooDB]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota Seed n.a. n.a. Database[FooDB]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota Plant n.a. n.a. Database[FooDB]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota Herb n.a. n.a. Database[FooDB]
NPO5665 Ulva pertusa Species Ulvaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO5665 Ulva pertusa Species Ulvaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO3809 Eucalyptus cladocalyx Species Myrtaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO5665 Ulva pertusa Species Ulvaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO4640 Portulaca oleracea Species Portulacaceae Eukaryota n.a. n.a. n.a. Database[TM-MC]
NPO997 Peltodon longipes Species Lamiaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO21925 Senecio serra Species Asteraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO17376 Bacillus amyloliquefaciens Species Bacillaceae Bacteria n.a. n.a. n.a. Database[UNPD]
NPO23741 Aspergillus violaceus Species Aspergillaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO21926 Pseudomonas aeruginosa Species Pseudomonadaceae Bacteria n.a. n.a. n.a. Database[UNPD]
NPO1920 Podocarpus elongata Species Podocarpaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO6621 Salvadora persica Species Salvadoraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO24252 Uvaria hamiltonii Species Annonaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO28694 Sanguisorba tenuifolia Species Rosaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO2853 Eschweilera coriacea Species Lecythidaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO23819 Baccharis peruviana Species Asteraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO24585 Ocotea macropoda Species Lauraceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO1520 Callyspongia pseudoreticulata Species Callyspongiidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO5665 Ulva pertusa Species Ulvaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO23713 Helina dubia Species Muscidae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO17526 Entada abyssinica Species Fabaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO21989 Uvaria tanzaniae Species Annonaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO23277 Lobophora papenfussii Species Dictyotaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO23507 Fissistigma balansae Species Annonaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO12670 Lactobacillus plantarum Species Lactobacillaceae Bacteria n.a. n.a. n.a. Database[UNPD]
NPO22861 Amansia glomerata Species Rhodomelaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO3809 Eucalyptus cladocalyx Species Myrtaceae Eukaryota n.a. n.a. n.a. Database[UNPD]
NPO23039 Turbo stenogyrus Species Turbinidae 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
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Inhibition = 86.2 % PMID[22356736]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. IC50 = 1100000.0 nM PMID[22356736]
NPT20529 Non-molecular NON-PROTEIN TARGET n.a. Inhibition = 0.0 % PMID[22356736]
NPT79 Organism Bacillus subtilis Bacillus subtilis MIC = 15.7 ug.mL-1 PMID[26099531]
NPT20 Organism Candida albicans Candida albicans Activity n.a. n.a. n.a. PMID[37506055]
NPT28797 Organism Cryptococcus neoformans Cryptococcus neoformans MIC = 50.0 ug.mL-1 PMID[37506055]
NPT564 Organism Listeria monocytogenes Listeria monocytogenes Activity = 86.9 % PMID[35724567]
NPT16 Organism Staphylococcus aureus Staphylococcus aureus MIC = 18.8 ug.mL-1 PMID[26099531]
NPT19 Organism Escherichia coli Escherichia coli MIC > 20.0 ug.mL-1 PMID[26099531]
NPT175 Organism Enterococcus faecalis Enterococcus faecalis MIC = 12.5 ug.mL-1 PMID[30528685]
NPT1724 Organism Dengue virus Dengue virus EC50 = 11200.0 nM PMID[31128447]
NPT17 Organism Staphylococcus epidermidis Staphylococcus epidermidis Activity = 82.0 % PMID[35724567]
NPT1248 Organism Serratia marcescens Serratia marcescens Activity = 53.5 % PMID[35724567]

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
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 NPC161774 and all remaining natural products in the NPASS database.
●  The right table: Most similar natural products (Tc>=0.5 or Top200).

Similarity Score Similarity Level Natural Product ID
1.0 High Similarity NPC256312
1.0 High Similarity NPC266888
1.0 High Similarity NPC10529
0.7143 Intermediate Similarity NPC84182
0.7143 Intermediate Similarity NPC128005
0.6757 Remote Similarity NPC214532
0.6757 Remote Similarity NPC76297
0.6757 Remote Similarity NPC196007
0.641 Remote Similarity NPC209156
0.5952 Remote Similarity NPC470783
0.5636 Remote Similarity NPC489594
0.5636 Remote Similarity NPC153491
0.5581 Remote Similarity NPC312315
0.5208 Remote Similarity NPC285926
0.5208 Remote Similarity NPC14672

Similar Clinical/Approved Drugs

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

●  The left chart: Distribution of similarity level between NPC161774 and all drugs/candidates.
●  The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

Similarity Score Similarity Level Drug ID Developmental Stage
0.5094 Remote Similarity NPD4780 Clinical (unspecified phase)

Bioactivity similarity

  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