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Decanoyl-Trp-Asn-Asp-Thr(1)-Gly-Orn-Asp-D-Ala-Asp-Gly-D-Ser-Glu(3S-Me)-Asp(Ph(2-Nh2))-(1)

Basic information

CPKB ID CP01207
IUPAC Name
(3S)-3-[[(2S)-4-amino-2-[[(2S)-2-(decanoylamino)-3-(1H-indol-3-yl)propanoyl]amino]-4-oxobutanoyl]amino]-4-[[(3S,6S,9R,15S,18R,21S,24S,30S,31R)-3-[2-(2-aminophenyl)-2-oxoethyl]-24-(3-aminopropyl)-15,21-bis(carboxymethyl)-6-[(2S)-1-carboxypropan-2-yl]-9-(hydroxymethyl)-18,31-dimethyl-2,5,8,11,14,17,20,23,26,29-decaoxo-1-oxa-4,7,10,13,16,19,22,25,28-nonazacyclohentriacont-30-yl]amino]-4-oxobutanoic acid
Synonyms
Bdbm50247922
Chembl1649722
Daptomycin
Schembl23046993
Source

Semi-synthetic [Division : Synthetic]

Wikipedia: Semi-synthetic

PubChem  

Function

Anti-Biotics   Anti-Gram+   PubChem  

Information

Daptomycin is an intravenously administered, broad spectrum antibiotic used to treat complex skin and tissue infections, endocarditis and bacteremia. Daptomycin is associated with a low to modest rate of serum enzyme elevations during therapy, but is a very rare cause of clinically apparent liver injury. Dechlorocuracomycin is a cyclic peptide found in several Streptomyces, consisting in the six following amino acids: D-valine, D-leucine, L-isoleucine, L-ornithine, L-beta-hydroxyasparagine and L-tryptophan. It has a role as a bacterial metabolite. It is an azamacrocycle, a homodetic cyclic peptide, a member of indoles and a primary amide. It contains a L-tryptophan residue, a L-ornithine residue, a L-isoleucine residue, a D-valine residue, a 3-hydroxy-L-asparagine residue and a D-leucine residue.

PubChem|25246315  

Legend

Structure

Download structure
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similarity structure
Molecular Formula

C72H101N17O26
Molecular Weight 1619.710366 g/mol
SMILES

RUN SEA Predictions

 CCCCCCCCCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]1C(=O)NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@@H]([C@@H](C)CC(=O)O)C(=O)N[C@@H](CC(=O)c2ccccc2N)C(=O)O[C@@H]1C  

PubChem|25246315
InChI
InChI=1S/C72H101N17O26/c1-5-6-7-8-9-10-11-22-53(93)81-44(25-38-31-76-42-20-15-13-17-39(38)42)66(108)84-45(27-52(75)92)67(109)86-48(30-59(102)103)68(110)89-61-37(4)115-72(114)49(26-51(91)40-18-12-14-19-41(40)74)87-71(113)60(35(2)24-56(96)97)88-69(111)50(34-90)82-55(95)32-77-63(105)46(28-57(98)99)83-62(104)36(3)79-65(107)47(29-58(100)101)85-64(106)43(21-16-23-73)80-54(94)33-78-70(61)112/h12-15,17-20,31,35-37,43-50,60-61,76,90H,5-11,16,21-30,32-34,73-74H2,1-4H3,(H2,75,92)(H,77,105)(H,78,112)(H,79,107)(H,80,94)(H,81,93)(H,82,95)(H,83,104)(H,84,108)(H,85,106)(H,86,109)(H,87,113)(H,88,111)(H,89,110)(H,96,97)(H,98,99)(H,100,101)(H,102,103)/t35-,36+,37+,43-,44-,45-,46-,47-,48-,49-,50+,60-,61-/m0/s1  
InChIKey
DOAKLVKFURWEDJ-DFQAAFHXNA-N
2D Structure
PubChem|25246315

Sequence

Graph alignment
Local alignment
IUPAC Condensed
decanoyl-Trp-Asn-Asp-Thr(1)-Gly-Orn-Asp-D-Ala-Asp-Gly-D-Ser-Glu(3S-Me)-Asp(Ph(2-NH2))-(1)  

PubChem|25246315
Amino acid chain
decanoyl--Trp--Asn--Asp--Thr(1)--Gly--Orn--Asp--D-Ala--Asp--Gly--D-Ser--Glu(3S-Me)--Asp(Ph(2-NH2))(1)  

CyclicPepedia|PP
Graph representation
decanoyl,Trp,Asn,Asp,Thr,Gly,Orn,Asp,D-Ala,Asp,Gly,D-Ser,Glu(3S-Me),Asp(Ph(2-NH2)) @4,13  

CyclicPepedia|PP
One letter code from Structure
WNDTGADADGSIA  

CyclicPepedia|Struct2seq
Amino acid chain from Structure
Ac-Trp--Asn--Asp--Thr(1)--Gly--Orn--Asp--Ala--Asp--Gly--Ser--3Me-Glu--CO(1)  

CyclicPepedia|Struct2seq
Description of the conversion sequence The one letter code and Amino acid chain derived from the structural transformation may be inconsistent, with the Amino acid chain containing Essential Amino acid and the one letter code not.

Chemical and Physical Properties

CyclicPepedia|Struc2Seq + PP

Structure Properties

Property Name Property Value
Exact Mass 1619.710366
Number of Rings 4.0
Complexity 0.547826087
XlogP3 AA -5.6218
Heavy Atom Count 115.0
Hydrogen Bond Donor Count 22.0
Hydrogen Bond Acceptor Count 24.0
Rotatable Bond Count 35.0
Property Name Property Value
Formal Charge 0.0
Refractivity 400.2605
Rule_of_Five 0.0
Number of Atoms 115.0
Topological Polar Surface Area 702.02
Refractivity 400.2605
Veber Rule 0.0
Ghose Filter 0.0
Property Name Property Value
RDKit Fingerprint
11100111110110101111110111110000111011101111100000111111111111101110101110101101111111010111100011110111110101111111011001110111010001111101111100011111001110010111001100011111110111001111001101110110101101101000000111000111010111000101010110101111011111101111000110011110001111101111111101000010000011111111100111010111110101110011111110010110111100011001111101001011111001000001111001111011000101000111100101001110010011110101101100111011111110100100011001010110111010111110010010001110001101010111110100101101011101111110110111001101101011100111100011011110101101111110010111111101011110111100101110111001110010011011110000111111110100101101101111110111111011010110111110111111010111011001011100111000100111100000010100011010101101110111111010010010011110101010111111010010000111011011011010011011011100011010111010111001111011110000101011101110111001110101111100100111110110101111101001111111111101101110111101110111011100010110110001011100111110011001111110010010011001010110001001111011110101001111011000111101111111111111111110111111110001101111010101101110111001100011010001100001110110101101011101100010001001111110011111101101010001011100111001111001101111110000101111011101011011011110100111111101110100001101010111100110111111010111111011011001100101101110101110011011110001011111111100111001111111111101101111000101100011011111111111101011011110110111110011110111111101101111111110011111011101011111111011101101100111101010011001111110110011111111111111111111111110110001110000111111111110000000110110110011101111100111011101010100111111110100010100100011101100011101001111011101100010000011110111101011111010100100111110111010010000011010010110011111000111010110010011111100010001110011111111110100111101000111000111101001100001110111011011011101111011010111101010000110100001111110100010101011111111101100100101111110111110100111111010001011110001011001011111111010010101001101111110111111111101011111011011010111011110011111110111010111111011011101011011011011101111110111001101111100110110010000001111101100010010100101011101011111
Morgan Fingerprint
0100000000100000000000000000000001000000010000010000000000000000100000000000000110000010001000000000010000000000000101010000000010100000000010000001000000000000000000000100000100000000000000000000000000010000000000000000001000000000010000000001000000100000000001010010000000000000000101000000001000000100001000000010000000000100100001000000000000000000000110000000100000000000100000000001010000000000000000000000000000001001000000000101000010000000000000000000000000000000000000000010000000001110000000010000000000000001000000000000000000011000000001010000000000000000000001000000000101000001100000000000000000000000000000000000000000000000000000001010000010000000010001000000000000001000000000100100000000000000010100000010001010000000100000000000001000000011000000000000000000000000000000000010000000000011000000001000000000000000100000000010000001000001001000001000000000110000000000010000010100000000000000100100000000000010000000000000010000100100011000000000000100000000000001001000000010001010010010100100000000010000
MACCS Keys
00000000000000000000000000000000000000000000000000000110010000000100000000000001101110000111100111001100110011110011111011010101110111011111111111110111111111111111110

Sequence Properties

Property Name Property Value
Boman Index 1.86230769230769
Instability -18.9615384615384
Charge -3.00067624814223
Aliphatic Index 53.076923076923

Binding Target

Other evidence

Property Name Property ID
TTD D05HPI
DrugMAP DMFDQ3I DMKDU16

Biologic Description

Toxicity PubChem|25246315

Elevations in serum aminotransferase levels occur in 2% to 6% of patients receiving daptomycin, rates that are minimally higher than with placebo or comparator drugs. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. Isolated case reports of possible liver injury from daptomycin have been reported, but serum bilirubin was normal in most cases, and the serum aminotransferase elevations were mild-to-moderate and typically accompanied by severe muscle injury with marked CK elevations. Such cases without jaundice or alkaline phosphatase elevations are more likely due to muscle rather than liver injury. Nevertheless, a few case reports of mild jaundice with a hepatocellular pattern of serum enzyme elevations and normal CK levels has been published. The latency to onset was 5 weeks, immunoallergic and autoimmune features were not present, and resolution was slow with mild abnormalities still present 6 weeks later. Thus, clinically apparent liver injury from daptomycin probably occurs, but is quite rare.

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Forecasting tools

Information Source

Reference

Pubmed_ID Title DOI Journal

1667253

 Effect of protein binding of daptomycin on MIC and antibacterial activity 10.1128/AAC.35.12.2505.

Antimicrob Agents Chemother

Effect of protein binding of daptomycin on MIC and antibacterial activity

Abstract

  • A higher rate of clinical failures in patients treated with daptomycin (2 mg/kg of body weight, given once daily) compared with rates in patients treated with conventional regimens caused early termination of this comparative clinical trial. One explanation for these failures could be that daptomycin is highly protein bound and that the concentration of the unbound active drug is too low for antibacterial activity. To assess this explanation, we studied the binding of daptomycin to proteins by using an ultrafiltration method. pH (7.0 to 7.4), temperature (25 or 37 degrees C), or daily freezing and thawing over 2 months had no effect on binding of daptomycin to proteins. We found that daptomycin was bound to albumin (90%) at 4 g/100 ml. Binding of daptomycin was not concentration dependent (2.5 to 80 micrograms/ml). In human serum samples spiked with daptomycin, average binding was 94% +/- 2.4%. In 6 subjects given an intravenous infusion of daptomycin (3 mg/kg), average binding was 90% +/- 2.1%. Susceptibility studies showed that a concentration in serum 20 times the unbound concentration was needed to equal the MIC of the total drug. These results indicate that daptomycin is highly bound (90 to 94%) to albumin and that clinical failure to daptomycin can in part be explained by the low concentration of the unbound drug.

28142234

 Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin 10.1021/acsinfecdis.7b00015.

ACS Infect Dis

Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin

Abstract

  • Daptomycin is a lipopeptide antibiotic that is highly bound to plasma proteins. To date, the plasma components and structure-activity relationships responsible for the plasma protein binding profile of daptomycin remain uncharacterized. In the present study we have employed a surface plasmon resonance assay together with molecular docking techniques to investigate the plasma protein binding structure-activity relationships related to the N-terminal fatty acyl of daptomycin. Three compounds were investigated: (1) native daptomycin, which displays an N-terminal n-decanoyl fatty acid side chain, and two analogues with modifications to the N-terminal fatty acyl chain; (2) des-acyl daptomycin; and (3) acetyl-daptomycin. The surface plasmon resonance (SPR) data showed that the binding profile of native daptomycin was in the rank order human serum albumin (HSA) ≫ α-1-antitrypsin > low-density lipoprotein ≥ hemoglobin > sex hormone binding globulin > α-1-acid-glycoprotein (AGP) > hemopexin > fibrinogen > α-2-macroglobulin > β2-microglobulin > high-density lipoprotein > fibronectin > haptoglobulin > transferrin > immunoglobulin G. Notably, binding to fatty acid free HSA was greater than binding to nondelipidated HSA. SPR and ultrafiltration studies also indicated that physiological concentrations of calcium increase binding of daptomycin and acetyl-daptomycin to HSA and AGP. A molecular model of the daptomycin-human serum albumin A complex is presented that illustrates the pivotal role of the N-terminal fatty acyl chain of daptomycin for binding to drug site 1 of HSA. In proof-of-concept, the capacity of physiological cocktails of the identified plasma proteins to inhibit the antibacterial activity of daptomycin was assessed with in vitro microbiological assays. We show that HSA, α-1-antitrypsin, low-density lipoprotein, sex hormone binding globulin, α-1-acid-glycoprotein, and hemopexin are responsible for the majority of the sequestering activity in human plasma. The findings are relevant to medicinal chemistry programs focused on the development of next-generation daptomycin lipopeptides. Tailored modifications to the N-terminal fatty acyl domain of the daptomycin molecule should yield novel daptomycin lipopeptides with more ideal plasma protein binding profiles to increase the levels of active (free) drug in plasma and improved in vivo activity.

32565355

 Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin 10.1016/j.xphs.2020.06.011.

J Pharm Sci

Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin

Abstract

  • Daptomycin, a cyclic lipopeptide antibiotic, is clinically used for the treatment of infections caused by Gram-positive bacteria, including the methicillin-resistant Staphylococcus aureus and the vancomycin-resistant Enterococci. While daptomycin shows high plasma protein binding (90-93%), our knowledge of the binding process is not extensive. To address this issue in more detail, we characterized the binding of daptomycin to plasma proteins and the findings indicate that the association constant for the binding of daptomycin to human serum albumin (HSA) is much higher than that for α-acid glycoprotein, another plasma protein. Daptomycin was also found to bind to a single site on HSA, which was identified as site II. The findings also suggest that the n-decanoyl moiety of daptomycin penetrates into the hydrophobic pocket of site II and that this acyl moiety interacts with Tyr411 at the entrance to site II. Due to this selective interaction with site II, daptomycin binding was significantly inhibited by drugs (ibuprofen or diazepam) and endogenous compounds (uremic toxins or fatty acids) which also strongly bind to site II. In diseased states, such an inhibition in the binding could result in the pharmacokinetics and therapeutic action of daptomycin being substantially altered.