INTRODUCTION:

Absorption, Distribution, Metabolism, and Extraction (ADME). Toxicology test are often a part of the process so it better pronounced as ADMET. Simply ADMET study finds how drug compound is processed by a living organism. For the ADMET study we choose a Stachys pilifera benth plant. For the detailed study of the plant we use to refer the review article ofHeibatollah Sadeghi¹. By using their isolated compounds, we get able to do further study of the components more than 300 annual or perennial species of Stachys pilifera benth are growing in temperate regions of southern Africa, the Mediterranean, America and Asia. Stachys pilifera is well known as Marsh kuhi².

It is endemic species from iron and it is found in mountainous habitats of zeros area³. The paper also provided the detailed information about the phytochemical ingredients present in the plant, various traditional uses, and some biological activities also it gives the information about photochemistry and pharma logical properties⁴. In the botany of the plant S. pilifera is the perennial and aromatic herb, belonging to the family lamiaceae. The plant has spicy flavour and aromatic sent⁵. The altitude ranges of this plant in mountainous area between 2200 and 3000 meters above the sea level.

The plant is a shrub with numerous stem 33to 43cm tall covered with soft hairy leaves. The flowers of the plant are pinkish white and 13 to 17mm long. The flowering time of the plant is late spring and summer. There are many traditional and ethnopharmalogical uses of the plant. In which some are mentioned here. The species of pilifera is widely used to treat various diseases in different regions of the world diseases like common cold, gastrointentional diseases, infections, cardic disorders, pain and brain injuries. Also the aerial part of the plant is used as herbal tea for treating asthma, rneumatoid arthritis and infections there are so many uses of the plant species⁶.

MATERIALS AND METHODS:

For ADME study we use free online web tool swiss ADME^8,9. At the top of the web page is accessible a black toolbar that lets the user navigate within the different SwissDrugDesing tool. There are a two boxes in which 1^stone is molecular sketcher it is based on ChemAxon’s Marvin JS allow to import, draw and edit a 2D chemical structure to be transferred to the SMILES list. In another box smiles developed in one line per molecule it is also editable text field. When the list of input is ready for submission we have to start SwissADME calculation by clicking on run button. Then all outputs are loaded in the same page as the input. Output panels compiling all the value for each molecule are filled immediately after calculation completion, one molecule after the other. This is way to use the ADME software, the result gives the information about Physiochemical properties, Lipophilicity, Water solubility, Pharmacokinetics and medicinal chemistry of the molecule. Also it shows the graphical representation in BOILED-Egg format it has four parameters BBB, HIA, PGP+ and PGP- as well it gives the remark for the molecule⁹.

The points located in the white ellipse represent compounds with high probability to be passively absorbed by the gastrointestinal tract. The point in yellow ellipseare for compounds with high probability to permeate through the BBB to access the CNS. White and yolk are not mutually exclusive. Molecule not predicted to be well absorbed nor BBB permeate are in grey zone. Point coloured in blue are for molecule predicted to be ⁷substrate of the P-gastrointestinal (PGP+) and hence actively pumped up from the brain or to the gastrointestinal lumen. If predicted non-substrate of the P-glycoprotein (PGP-), the related point is in red.¹⁰

Structure and bioavailability radar:

The hexagon structure which is hallow on the outside and pink on the inside called bioavailability radar the colour separation of this hexagon is defined boundary for the prediction¹¹. It is the first section which includes 2D chemical structure with canonical SMILES which situated below the title. Bioavailability radar is displayed for a rapid evaluation of drug-likeness of interest which considered six physiochemical properties LIPO (Lipophilicity), FLEX (flexibility), INSATU (Instauration), INSOLU (Insolubility), SIZE, POLAR (Polarity)¹². Each physiochemical property has definite range, the pink area in which the radar plot of the molecule has to fall entirely to be considered drug-like. Lipophilicity; XLOGP3 between -0.7 and +0.5, size: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 0A2, solubility: log S not higher 6, saturation: fraction of carbon in sp3 hybridisation not less than0.25 and flexibility: no more than 9 rotatable bonds. There are 4 tabs located on the top corner with the help of them we can also submit the molecule to other Swiss Drug Design tools.¹³

Physiochemical properties:

Simple physiochemical and molecular descriptions are mentioned here. It includes molecular formula, molecular weight, number of heavy atoms present in molecule, number of aromatic heavy atoms, fraction Csp3 value, number of rotatable bonds, number of hydrogen bond acceptor and donors, molar refractivity value and TPSA (Topological polar surface area. The values are computed with Open Babel, version 2.3.0.

Lipophilicity:

It is very substantial property of drug discovery. It gives most important and informational physiochemical property in medicinal chemistry. The logarithum of octanol/water partition coefficient is a well-known measure e of molecular lipophilicity. It is used to assess biological properties relevant to drug action, such as lipid solubilty, tissue distribution, receptor binding, cellular uptake, metabolism and bioavailability. Large the LOGP value also increases the lipophilicity. To identify the lipophilicity character in compound swiss ADME provide 5 freely available models they are XLOP3, WLOGP, MLOGP, SILICOS-IT and iLOGP. XLOGP3 it is an atomistic method including corrective factor and knowledge based library developed by cheng et al. 2007. WLOGP it is an application of purely atomistic method based on fragmental method. MLOGP it is an archetype of topological method relying on the linear relationship with 13 molecular descriptors implemented as per researchers. SILICOS-IT a hybrid method relying on 27 fragments and 7 topological descriptors, and last is ilogp a physics based method lean on free energies of solvation in n-octanol and water calculated by the generalized born and solvent accessible surface area (GB/SA) model. Consensus logp o/w is an arithmatric mean of the value predicted by the five proposted method¹⁴.

Water solubility:

Water solubility is the important factor for drugs activity. The phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired pharma logical response. The solubility of a compound depends on the ambient temperature pressure and solvent used. Soluble molecule is good for many drug development activities because it easy for handling and formulation it is also easy for absorption. The drug is measured highly soluble when the highest dose strength will be soluble in 250ml over the pH reng is between 1to 7.5 less of aqouse medium. Swiss ADME include two topological approaches to predict water solubility in this 1^st one is the application of ESOL model (Solubility class: log S Scale: Insoluble <-10, poorly <-6, moderately <-4, soluble <-2 ,very <0 <highly) and the 2^nd one is adapted from Ali et al., 2012 (Solubility class: Log S Scale: Insoluble< -10, poorly <-6, moderately <-4, soluble <-2, very <0 <highly) both are differ from the fundamental general solubility equation since they avoid the melting point parameter but the linear correlation between predicted and experimental values were strong (R2 = 0.69 and 0.81 respectively). The 3^rd predictor of Swiss ADME was developed by SILICOS-IT, where the linear coefficient is corrected by molecular weight (R2=0.75). All predicted values are the decimal logarithm of the molar solubility in water (log S). Swiss ADME also provides solubility in mol/l and mg/ml along with qualitative solubility classes.¹⁵

Pharmacokinetics:

It is very important feature for drug design and development. It explains what the body does to a drug. It involves the process of uptake of drug by the body, an absorption, a metabolism in the tissues, and then the excretion of the drug from the body. The delineation, exists in a region of agreeable properties for GL absorption on the plot of two computed descriptors; ALOGP versus PSA. The region most populated by well absorbed molecule is elliptical, it is call Egan egg, which is used to assess the predictive power of the model for GI passive absorption and prediction for brain access by passive diffusion to finally lay the BOILED-Egg model produce a rapid, spontaneous, effectively imitate yet boisterous method to forecast the passive GI absorption helpful for drug discovery and development. The white region is the space of the molecules with greater extent of absorption by GI tract, the yellow region (yolk) is the space with highest probability to permeate to the brain. cytochrome p450 (CYP) isoenzymes biotransforms more than 50-90% of therapeutic molecules forms its five major isoforms (CYP1A2, CYP3A4, CYP2CP, CYP2C19, CYP2D6). P-gp is broadly dispersed in intestinal epithelium which pumps xenobiotic back in to theintestinal lumen and form the capillaries. Swiss ADME adopts support vector machine alogarithum (SVM) for the datasets of known substrate/ non substrates or inhibitors/ non inhibitors for binary classification. The resultant molecule will return yes or no if the molecule under investigation expected to be substrate for both P-gp substrate was built on 1033 molecules and tested on 415 molecules.¹⁶

Medicinal chemistry:

The purpose of the section is to support medicinal chemist in their daily drug discovery endeavours. To coomplementory pattern recoginaton methods allows for identification of potentially problematic fragments. PAINS (For Pan assay interference compounds, a.k.a frequent hitters or promiscuous compounds) are molecules containing substructures showing potent response in assays irrespective of the protein target. Such fragments, yielding false positive biological outputs. We implemented structural alert, which consist in a list of 105 fragments identified by Brenk et.al. 5. to be putatively toxic, chemically reactive, metabolically unstable or to bear properties responsible for four pharmacokinetics. In swissADME it possible to have a chemical description of the problematic fragment found in a given molecule by flying over the “question mark“ icon appering after the fragment list. This is implemented for both plains and brenk filters by applying these and other physicochemical filters to design scrinning liblaries, brent et al 5 observed that most of the reamianing compounds satisfy craiteria for “leadlikness” this concept is similar to drug likness, yet focusing on physicochemical boundaries defining a good lead that is a molecule entry suitable for optimisation. By definition leads are subjected to chemical modification that will most likely increase size and lipophilicity as a consequence says leads are required to be smaller and less hydrophobic than drug like molecules. Since it is crucial for a chemist to judge to whether a given molecule is suitable to initiate lead optimization in addition to structural filters be implemented a rule based method for lead likeness.¹⁹

RESULT:

We studied all 16 molecules present in the S. pilifera benth the results of the molecules are as follows:

Thymol, Myrtenyl acetate, Caryophyllene oxide, Beta-caryophyllene, Spathulenol, Limonene, Cis—cherysanthenyl acetate, Linolool, Terpinen-4-ol, Viridiflorol, Alpha-curcumene, 1,8-Cineole, Chrysanthenol, Trans-verbenol, are orally bioavailable.

Hexadeca-2,6,10,14-tetren-1-ol,3,7,11,16-tetramethyl and Linolenic acid are not orally bioavailable because it is too flexible and Linolenic acid is too lipophilc also.

Fig 1: BOILED-EGG for prediction of GI Absorption and brain Penetration

The analysis predict that the phytoconstituent shows GI absorption with nearly 80% of the molecules exhibiting BBB penetration and all are predicted as the nonsubstrates of P-gp (PGP-)

Thymol has high GI absorption and, Myrtenyl acetate, Caryophyllene oxide, Beta-caryophyllene, Spathulenol, Limonene, Cis—cherysanthenyl acetate, Linolool, Terpinen-4-ol, Viridiflorol, Hexadeca-2,6,10,14-tetren-1-ol,3,7,11,16-tetramethyl, Linolenic acid, 1,8-Cineole, Chrysanthenol, Trans-verbenol, having GI or intestinal absorption

CONCLUSION:

Plants are an integral part of our earth. Almost every part of the plants has different importance, but the more important factor is the medicinal properties found in the plants. Ayurveda originated from the fact that plants were used to cure diseases from ancient times. In this, there is a large number of medicines made from plants, Time has changed, the nature of diseases has changed, and the method of treatment has changed, and there has been a lot of progress in science, technology, and medicinal chemistry, but making medicine using the chemical compound found in plants is still the same. Our effort in this project is to study the chemical, physical and, ADME properties of an already isolated plant so we can make a drug or medicine better than before. To study the ADMET we use the online software Swiss ADME, by drawing the molecular structure of a particular molecule we get able to know the different kinds of parameters of the compound which is important and helpful for medicinal studies. It not only provides huge information about pharmaceutical properties but also it saves lot of time and money. The phytoconstituents of stchys pilifera benth were analysed can be used as a monographs by researchers and scientists for the development of potential semisynthetic and synthetic drug for multifarious usage.

ACKNOWLEDGMENTS:

The authors express sincere gratitude towards Management, Principal, Anekant Education Society’s Tuljaram Chaturchand College Baramati. Head, and P.G. Coordinator Department of Chemistry and ARC T.C. College for facility and financial support. The authors are also grateful to coordinator, CFC for HPLC and FTIR analysis.

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Received on 17.06.2023 Modified on 23.10.2023

Res. J. Pharmacognosy and Phytochem. 2024; 16(2):78-82.

DOI: 10.52711/0975-4385.2024.00015

Molecule name	Bioavailability radar	Result
Thymol		In this example the compound is predicted to be orally bioavailable
Myrtenyl acetate		In this example the compound is predicted to be orally bioavailable