Pharmacokinetic screening to Estimate the drug likeliness characteristics of selected Herbal Anticancer Drugs
1Department of Pharmacology, Institute of Medical Sciences, BHU, Varanasi, India.
2Department of Medicine, Institute of Medical Sciences, BHU, Varanasi, India.
3Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute, Faridabad, Haryana, India.
*Corresponding Author E-mail: asthwal@rediffmail.com
ABSTRACT:
The pharmacokinetic parameters of a drug plays a very essential role in determining the therapeutic success of an experimental compound, so it is one of the aspects of drug discovery which are essential to be determined in the early phases. The pharmacokinetic studies further help the drug discovery team to optimize their in vivo pharmacokinetic and drug safety bioassays.Low solubility, low absorbency, and chemical instability can seriously affect bioassay results. Today a lot of computational software are available which use their algorithms to calculate the pharmacokinetic parameters of the selected compounds and hence may help the drug discovery team to move in a direction where the chances of getting a good clinical candidate are higher. This paper presents the screening of nine selected herbal anticancer agents (Catechin, Cinnamaldehyde, Epicatechin, Eugenol, Oxyresveratrol, Quercetin, Crocin, Kaempferol, and Emodin) based upon their pharmacokinetic properties with the help of Discovery Studio 2.5. The main parameters which are estimated under this pharmacokinetic ADMET (absorption, distribution, metabolism, excretion and toxicity) study are aqueous solubility, human intestinal absorption, plasma protein binding (PPB), blood-brain-barrier (BBB) penetration, cytochrome P4502D6 inhibition and hepatotoxicity levels. Four compounds (Cinnamaldehyde, Eugenol, Crocin and Oxyresveratrol) were found to possess the required pharmacokinetic properties and are suitable for further anticancer in vivo and in vitro analysis.
KEYWORDS: Pharmacokinetics, Anticancer, Plasma protein binding, Hepatotoxicity, Aqueous solubility.
INTRODUCTION:
The mechanisms that determine pharmacokinetics are absorption, distribution, metabolism, and excretion (ADME)1. Drug's pharmacokinetic (PK) properties have long been a matter of priority in the drug development process, those compounds that show sufficient acceptable ADME and toxicity characteristics, to survive human Phase I clinical trials are considered drug-like.
Drug pharmacokinetic properties arean important part of pharmaceutical research. Drug characteristics are used to pick "hits" that are good beginning points for research on a new clinical candidate in the early stages of drug discovery.
They aid in directing the drug discovery team to design compounds with a higher chance of success in terms of PK and safety. In the later stages of drug discovery, more focus is placed on understanding the structure-activity relationship (SAR)2, directing structural alterations for property optimization, identifying the reasons for poor PK and toxicity, optimizing and interpreting bioassays, and constructing prospective models of human PK and its link to pharmacodynamics (PD)3. In one such kind of study pyrimidine analogs were prepared with the help of 3D-QSAR (Three dimensional Quantitative structure activity relationship) and pharmacophore modelling4. A drug discovery team's ultimate objective is to find an effective clinical candidate that can be turned into a useful therapeutic product. Appropriate PK performance is a key requirement in the drug discovery team's profile for a new medicinal product.
The current treatment of cancer comprises combination therapies like chemotherapy, radiotherapy, and immunotherapy5. Chemoprevention is recognized as an important approach to cancer management6. There are many disadvantages of chemotherapy like side effects7, resistance to the drugs, and the need for other types of therapy in combination with chemotherapeutic agents to achieve the desired therapeutic effect.
Natural phytoconstituents can be used to cure a wide variety of ailments8. Natural products account for more than half of all modern drugs in clinical use since ancient times9,10. Some herbal medications have been used to treat diseases, such as digoxin for congestive heart failure, reserpine as an antihypertensive, vincristine as an antineoplastic, resveratrol as antioxidant11, cutrcumin-3 as anti-inflammatory agent12, and artemisinin as an antimalarial. Various phytoconstituents discovered in recent years have demonstrated different pharmacological properties13. So, there is a need to screen large amount of natural products for lead compound identification. The use of virtual screening of natural products is becoming a vital tool for assessing their physicochemical characteristics in a rapid and cost-effective manner14. Thus, in the present research work, ADMET (absorption, distribution, metabolism, excretionandtoxicity) Studies (virtual screening) have been used to identify potential phytoconstituents based on their drug-likeliness characteristics/properties.
MATERIALS AND METHODS:
Preparation of ligand:
Molecular docking study was conducted on the selected natural products against CyP D (Cyclophilin D) as the target in one of our previous natural anticancer studies15. Therefore, the present study plans to use these compounds as ligands for the estimation of their pharmacokinetic characteristics by the ADMET study. The Ligands used in this study wereCatechin, Cinnamaldehyde, Epicatechin, Eugenol, Oxyresveratrol, Quercetin, Crocin, Kaempferol, and Emodin. Their structures were retrieved from the PubChem database (www.pubmed.com) as an sdf file. Further, compounds were prepared for ADMET study with the help of prepare ligands protocol of the Discovery Studio 2.5. The 2D structure of the selected ligands is presented in Table 1.
ADMET Prediction:
The ADMET characteristics of the selected ligands were predicted with the help of the ADMET prediction tool and then it is compared with the standard descriptor values for Discovery Studio 2.516. In this study, the various pharmacokinetic parameters like Aqueous solubility, Human intestinal absorption, Plasma protein binding (PPB), Blood-brain-barrier (BBB) penetration, Cytochrome P4502D6 inhibition, and Hepatotoxicity levels were estimated for nineselected ligands.
RESULT:
According to the ADMET prediction, four of the nine compounds had high penetration capacity, while five had medium penetration capacity. Three of the nine compounds fell outside the 99% BBB confidence ellipse. All nine compounds were inside the 99% absorption ellipse, so they were expected to possess good HIA (Human Intestinal Absorption).
Standard levels of ADMET descriptors are calculated using Discovery Studio 2.5 software (Table 3). Table 2 describes calculated ADMET descriptors for all the nine compounds. The solubility of the tested compounds ranged from very poor to good. The aqueous solubility of eight of the nine compounds was good. Many xenobiotics are metabolised by Cytochrome P450 2D6 (CYP2D6), and inhibiting it with a drug can result in serious drug-drug interactions. As a result, determining CYP2D6 inhibition is a vital step in the drug development and discovery process. Four compounds out of nine, work as non-inhibitors, and five work as inhibitors. The hepatotoxicity model predicts the incidence of dose-dependent human toxicity. Three of the nine compounds were classified as non-hepatotoxic byusing the Discovery Studio 2.5 Hepatotoxicity model. The pharmaceutical activity is determined by the free drug concentration; therefore, the possible plasma protein binding of compounds must be considered. Three of the nine tested compounds were likely to be <90% binding, two were likely to be ≥90% binding, and four were likely to be ≥95% binding.
Figure 1: Plot of the two-dimensional polar surface area (PSA_2D) vs. the calculated ALogP98 for nine natural compounds
Table 1: Phytoconstituents used as ligand.
|
S. No |
Structure |
PubChem CID Number |
Name |
|
1 |
|
CID 73160 |
Catechin |
|
2 |
|
CID 637511 |
Cinnamaldehyde |
|
3 |
|
CID 72276 |
Epicatechin |
|
4 |
|
CID 3314 |
Eugenol |
|
5 |
|
CID 5280863 |
Kaempferol |
|
6 |
|
CID 5281717 |
Oxyresveratrol |
|
7 |
|
CID 5280343 |
Quercetin |
|
8 |
|
CID 5281233 |
Crocin |
|
9 |
|
CID 3220 |
Emodin |
Table 2: The absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions for 9 selected compounds.
|
Compound |
BBB Level |
Absorption Level |
Solubility Level |
Hepatotoxicity Level |
CYP2D6 Level |
PPB Level |
|
Catachin |
4 |
0 |
3 |
1 |
1 |
0 |
|
Cinnamaldehyde |
1 |
0 |
3 |
0 |
0 |
0 |
|
Epicatachin |
4 |
0 |
3 |
1 |
1 |
0 |
|
Eugenol |
1 |
0 |
3 |
0 |
0 |
2 |
|
Oxyresveratrol |
3 |
0 |
3 |
1 |
0 |
1 |
|
Quercetin |
4 |
1 |
3 |
1 |
1 |
2 |
|
Crocin |
1 |
0 |
1 |
0 |
0 |
1 |
|
Kaempferol |
3 |
0 |
3 |
1 |
1 |
2 |
|
Emodin |
3 |
0 |
3 |
1 |
1 |
2 |
Table 3: Standard levels of ADMET descriptors according to Discovery Studio 2.5.16
|
Aq. Solubility and Drug Likeness |
BBB |
Cytochrome P450-14DM |
Hepatotoxicity |
Human Intestinal Absorption |
||||||
|
Level |
Intensity |
Level |
Intensity |
Level |
Value |
Level |
Value |
Level |
Value |
|
|
0 |
Extremely low |
0 |
Very high |
0 |
Non inhibitor |
0 |
Non toxic |
0 |
Good |
|
|
1 |
No, very low |
1 |
High |
1 |
Inhibitor |
1 |
Toxic |
1 |
Moderate |
|
|
2 |
Yes, low |
2 |
Medium |
PPB |
2 |
Poor |
|
|||
|
3 |
Yes, good |
3 |
Low |
Level |
% of biding |
3 |
Very poor |
|
||
|
4 |
Yes, optimal |
4 |
Very low |
0 |
<90% |
|
|
|||
|
5 |
No, too soluble |
5 |
Warning: molecules with one or more unknown AlogP calculation |
1 |
>90% |
|
||||
|
6 |
Unknown |
|
|
2 |
>95% |
|
|
|||
DISCUSSION:
A significant number of cancer patients receive chemotherapy or chemoradiation therapy and get benefited from anticancer drug treatment. But, it is also seen that some anticancer drugs are very toxic to normal cells and tissues, they cause a variety of side effects including nausea, vomiting, loss of appetite, diarrhoea, oral mucositis, and hearing loss. These side effects frequently reduce the patient's quality of life (QOL) and make it difficult to continue with chemotherapy or chemoradiotherapy. As a result, the development of new therapeutic drugs with no or less amount of side effects is warranted17.In this study, the pharmacokinetic profile of all the selected nine herbal drugs was estimated with the help of the ADMET prediction tool of Discovery Studio 2.5 software. Under this estimation, a biplot (Figure 1) is made that depicts the corresponding 95% and 99% confidence ellipses for the human intestinal absorption (HIA) and blood-brain barrier (BBB) models. Polar surface area (PSA) is inversely proportional to percent HIA and therefore inversely proportional to cell wall permeability. In general, we use log P to estimate a compound’s lipophilicity. As a result, for accurate prediction of the compounds' cellular permeability, a model with descriptors Atom-based Log P98 (ALogP98) and two-dimensional PSA (PSA 2D) with a biplotincluding 95% and 99% confidence ellipses was used18. All of the compounds fall under a 99% absorption ellipse but when we observe a 95% ellipse quercetin was an exception. It is also observed thatsix compounds fall under the 99% BBB ellipse and only four compounds are inside the 95% ellipse.
CONCLUSION:
In summary, findings showed that four natural products Cinnamaldehyde, Eugenol, Crocin, and Oxyresveratrol have the potential to act as suitable drug candidates. These compounds have shown a better ADMET profile than the other five compounds. Therefore, it is worth mentioning that these phytoconstituents could serve as potential anticancer drugs by virtue of their better drug-likeliness characteristics.
CONFLICT OF INTEREST STATEMENT:
None to declare
ACKNOWLEDGMENT:
Funding support for this work includes ICMR and BHU-UGC. We thank the Institute of Medical Sciences, Banaras Hindu University,Varanasi, India for providing the infrastructure, Ph.D. fellowship and other research facilities.
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Received on 25.06.2022 Modified on 09.09.2022
Accepted on 15.10.2022 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(7):3422-3426.
DOI: 10.52711/0974-360X.2023.00566