記住我
The starting molecular structures of the marine cyclopeptides to be studied were obtained from ChemSpider (https://www.chemspider.com), which is a chemical structure database available online that provides fast structure search access to millions of structures from many data sources, with information related to physical, chemical, and biological properties, interactive spectra and literature references. The graphical sketches of the molecular structures of the Homophymines A–E and A1–E1 are displayed in Figure 1.
Chemoinformatics and BioactivityA compact representation of the information related to bioavailability may be displayed in a graphic way through the so-called Bioavailability Radars which are shown in Figure 2 for the Homophymines family of antimicrobial marine cyclopeptides:
Bioavailability radars of the Homophymine Family of Antimicrobial Marine Cyclopeptides.
It can be appreciated that more important problems for the Homophymines family of antimicrobial marine cyclopeptides for their consideration as therapeutic drugs of easy availability are related to their size, polar character, and flexibility.
The Bioactivity Scores, that is a measure of the ability of the molecules to behave or interact with different receptors, for the Homophymines A–E and A1–E1 are presented in Table 1, while a graphical representation is displayed in Figure 3, as the corresponding Biological Targets.
Table 1. Bioactivity Scores of the Homophymines Family of Antimicrobial Marine Cyclopeptides Calculated based on the GPCR Ligand, Ion Channel Modulator, Nuclear Receptor Ligand, Kinase Inhibitor, Protease Inhibitor, and Enzyme Inhibitor Interactions.Property
A
B
C
D
E
A1
B1
C1
D1
E1
GPCR Ligand
−3.99
−3.99
−3.99
−4.00
−4.00
−3.99
−3.99
−3.99
−4.00
−4.00
Ion Channel Modulator
−4.04
−4.03
−4.04
−4.04
−4.05
−4.04
−4.03
−4.04
−4.04
−4.05
Nuclear Receptor Ligand
−4.05
−4.05
−4.06
−4.06
−4.06
−4.05
−4.05
−4.06
−4.06
−4.06
Kinase Inhibitor
−4.05
−4.05
−4.06
−4.06
−4.06
−4.06
−4.05
−4.06
−4.06
−4.06
Protease Inhibitor
−3.94
−3.93
−3.94
−3.95
−3.95
−3.94
−3.93
−3.94
−3.95
−3.95
Enzyme Inhibitor
−3.99
−3.99
−4.00
−4.00
−4.01
−4.00
−3.99
−4.00
−4.00
−4.01
Predicted biological targets of the Homophymines family of antimicrobial marine cyclopeptides.
It can be concluded that the main interaction for all the members of the Homophymine family of antimicrobial marine cyclopeptides will be behaving as protease inhibitors with little differences between them.
An ADMET study is the assessment of pharmacokinetics of a drug which stands for Absorption, Distribution, Metabolism, Excretion and Toxicity. The prediction of the fate of a drug and the effects caused by a drug inside the body, such as how much drug is absorbed if administered orally and how much is absorbed in the gastrointestinal tract, is an indispensable part of drug discovery. In a similar way, if the absorption is poor, its distribution and metabolism would be affected, which can lead to causing neurotoxicity and nephrotoxicity. Ultimately, the study is to understand the disposition of a drug molecule within an organism. Thus, ADMET study is one of the most essential parts of computational drug design.
The computed ADMET properties of the Homophymines family of antimicrobial marine cyclopeptides are presented in Table 2.
Table 2. Computed ADMET Properties of the Homophymines Family of Antimicrobial Marine Cyclopeptides.
Absorption
Property
A
B
C
D
E
A1
B1
C1
D1
E1
Caco-2 Permeability
−0.31
−0.79
−0.62
−0.82
−0.68
−0.39
−0.58
−0.48
−0.47
−0.40
Intestinal Absorption
0
0
0
0
0
0
0
0
0
0
Skin Permeability
−2.74
−2.74
−2.74
−2.74
−2.74
−2.74
−2.74
−2.74
−2.74
−2.74
P-glycoprotein Substrate
Yes
No
No
No
No
Yes
Yes
Yes
Yes
Yes
P-glycoprotein I Inhibitor
No
No
No
No
No
No
No
No
No
No
P-glycoprotein II Inhibitor
No
No
No
No
No
No
No
No
No
No
Distribution
Property
A
B
C
D
E
A1
B1
C1
D1
E1
VDss
−0.45
−0.53
−0.51
−0.46
−0.45
−0.30
−0.33
−0.30
−0.35
−0.31
Fraction Unbound
0.29
0.33
0.33
0.34
0.34
0.34
0.33
0.35
0.33
0.34
BBB Permeability
−3.60
−4.47
−4.38
−4.53
−4.43
−3.63
−4.04
−3.70
−3.80
−3.83
CNS Permeability
−6.47
−6.63
−6.62
−6.66
−6.61
−6.76
−6.65
−6.82
−6.55
−6.64
Metabolism
Property
A
B
C
D
E
A1
B1
C1
D1
E1
Substrate
CYP2D6
No
No
No
No
No
No
No
No
No
No
CYP3A4
No
No
No
No
No
No
No
No
No
No
Inhibitor
CYP1A2
No
No
No
No
No
No
No
No
No
No
CYP2C19
No
No
No
No
No
No
No
No
No
No
CYP2C9
No
No
No
No
No
No
No
No
No
No
CYP2D6
No
No
No
No
No
No
No
No
No
No
CYP3 A4
No
No
No
No
No
No
No
No
No
No
Excretion
Property
A
B
C
D
E
A1
B1
C1
D1
E1
Total Clearance
−2.17
−1.94
−1.85
2.27
−2.05
−2.09
−1.94
−2.23
−2.30
2.24
Renal OCT2 Substrate
No
No
No
No
No
No
No
No
No
No
Toxicity
Property
A
B
C
D
E
A1
B1
C1
D1
E1
AMES Toxicity
No
No
No
No
No
No
No
No
No
No
MRTD
0.45
0.44
0.43
0.44
0.44
0.47
0.46
0.47
0.46
0.467
hERG I Inhibitor
No
No
No
No
No
No
No
No
No
No
hERG II Inhibitor
No
No
No
No
No
No
No
No
No
No
ORAT
2.48
2.48
2.48
2.48
2.48
2.48
2.48
2.48
2.48
2.48
ORCT
6.29
6.91
6.77
7.13
6.97
6.97
7.37
6.54
7.84
6.9
Hepatotoxicity
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Skin Sensitisation
No
No
No
No
No
No
No
No
No
No
T. Pyriformis Toxicity
0.29
0.29
0.29
0.29
0.29
0.29
0.29
0.29
0.29
0.29
The Caco-2 cell monolayer is commonly employed as an in vitro model of the human intestinal mucosa to predict medication absorption when given orally. A compound is considered to have a high Caco-2 permeability has a Papp >8×10−6 cm/s. Thus, high Caco-2 permeability would translate in predicted values >0.90, presenting the Homophymines A–E and A1–E1 values much lower than the ideal one. The Intestine is normally the primary site for absorption of a drug from an orally administered solution and the Intestinal Absorption (IA) parameter predicts the percentage of a drug absorbed through the human intestine. An absorbance of less than 30 % is considered poor. From Table 2, all the Homophymines A–E and A1–E1 will not be absorbed. P-glycoprotein functions as a biological barrier by extruding toxins and xenobiotics out of cells. The model predicts whether a given compound is likely to be a substrate of Pgp or not. The prediction is in the positive direction for Homophymines A and A1–E1 and negative for Homophymines B–E. Modification of P-glycoprotein- mediated transport has significant pharmacokinetic consequences for Pgp substrates, which might be employed for specific therapeutic benefits or create contraindications.
Thus, this study predicts that all the antimicrobial peptides considered in this study will not act as P-glycoprotein I and II inhibitors. Also, it can be predicted whether a given compound is likely to be skin permeable. If a compound's log Kp is more than −2.5, it is said to have low skin permeability. It means that all cyclopeptides could be of interest for the development of transdermal drug delivery.36
The total dose of a drug requires a volume to be uniformly in blood plasma which is named VDss. The drug will be more distributed in the tissue rather than in the plasma for higher VDss. VDss is estimated low when log VDss<−0.15 and high when log VDss>−0.45) implying that for the Homophymines A–E the values for VDss are high while they are low for the Homophymines A1–E1. The degree to which a medicine binds proteins in the blood can impair its efficacy, as the more bound it is, the less efficiently it can pass cellular membranes or diffuse. The Fraction Unbound predicts the fraction that will be unbound in plasma resulting in the values shown in Table 2. The ability of a medicine to pass the blood-brain barrier is an important feature to examine to avoid side effects and toxicities. The logarithmic ratio of brain to plasma drug concentrations is used to calculate permeability. A logBB>−0.3 indicates that a substance can easily penetrate the blood-brain barrier, whereas molecules with a logBB>−1 are poorly distributed to the brain. Another measurement is the blood-brain permeability-surface area product (logPS) or CNS Permeability. It is predicted that the Homophymines A–E and A1–E1 will be unable to penetrate the CNS.36
Because it oxidizes xenobiotics to promote excretion, Cytochrome P450 is a key detoxification enzyme in the body, primarily found in the liver. Many medicines are destroyed, and some are activated by the cytochrome P450 iso- forms. As a result, determining a compound's capacity to inhibit cytochrome P450 is critical. If the concentration required to achieve 50 % inhibition for each isoform is less than 10 μM, the substance is termed a cytochrome P450 inhibitor. As can be seen from Table 2, all the cyclopeptides are predicted as not being P450 inhibitors for any isoform. It is al important to know if a given compound is likely to be a cytochrome P450 substrate. The prediction indicate that this will be not the case for any of the cyclopeptides.36
Hepatic clearance and renal clearance combine to form drug clearance (Cltot) (excretion via the kidneys). It has something to do with bioavailability and is crucial in setting dose rates. The predicted Total Clearance Cltot for the Homophymines A–E and A1–E1 are given in log(ml/min/kg). OCT2 is a renal uptake transporter that plays an important role in disposition and renal clearance of drugs. It is predicted that all the cyclopeptides considered in this study will not behave as an OCT2 substrate.36
The AMES test is a widely used bacteria-based method for determining a compound's mutagenic potential. A positive test indicates that the substance is mutagenic and so could cause cancer. All of the compounds under investigation have unfavorable predictions. The maximum recommended tolerated dose (MRTD) is a measure of a chemical's hazardous dosage threshold in humans. The MRTD is low for all the Homophymines A–E and A1–E1. The Inhibition of the potassium channels encoded by hERG are the principal causes for the development of acquire long QT syndrome, thus leading to fatal ventricular arrhythmia. The predictions indicate that all the cyclopeptides are unlikely to be a hERG I or II inhibitor. The lethal dosage values (LD50) are a standard measurement of acute toxicity and is defined as the amount of a compound that causes the death of 50 % of a group of test animals. The predicted values are given in mol/kg. Chronic studies are designed to determine the lowest dose of a chemical that causes an unfavorable impact (LOAEL) and the highest dose at which no adverse effects are seen (NOAEL). In this case, the predicted values are given in log(mg/kg-bw/lday). Drug-induced liver injury is a major safety concern for drug development and a significant cause of drug attrition. Thus, Hepatoxicity is associated with disrupted normal function of the liver and the predicted values for all the cyclopeptides are positive. On the other hand, the predicted values for Skin Sensitization are negative. T. Pyriformis is a protozoa bacterium, with its toxicity often used as a toxic endpoint. For the Homophymines A–E and A1–E1, the plGC50, which is the negative logarithm of the concentration required to block 50 % growth (a value>−0.5 log μg/L is considered hazardous), has been predicted.36
Conceptual DFT CalculationsThe optimized molecular structures of the Homophymines A–E and A1–E1 marine cyclopeptides calculated according to the procedure presented in the Materials and Methods section are displayed in Figure 4.
Optimized molecular structures of the Homophymines family of antimicrobial marine cyclopeptides.
By considering an in-house software tool for the estimation of the the KID parameters of the Homophymines A–E and A1–E1 cyclopeptides on the basis of the electron densities generated through the high-level calculations, the global reactivity descriptors (including the Nucleophilicity N) have been determined which results are displayed in Table 3.
Table 3. Global
留言 (0)