Introduction

Urinary tract infection is defined as when a uropathogen is successful to overcome the host immune response and able to colonize the urinary tract. UTI most common bacterial infection affecting huge population worldwide.¹ Good hygiene, probiotics, antibiotic, probiotics and vaccines are the potential remedies to treat the chronic and recurrent UTIs. Antibiotics are most common treatment for UTI . With alarming rates of multi drug resistance pattern in uropathogen that hinders the treatment of UTI demands an alternative option with no side effects, cost effective treatment. Many studies reported that for the acute UTI,  natural therapeutics like cranberry, berberine, estriol cream, uva ursi, supplements of vitamin A, C and potassium salt are prescribed.² There are many studies which reported cranberry efficacy in clinical trial to treat the urinary tract infection.³ Antibiotics  are the major therapy for the prevention and treatment of the uncomplicated and complicated UTI. Uropathogens evade the immune responses  to survive via  different mechanism involving morphological variation, biofilm formation and able to invade the uroepithelial cells in bladder. Adhesive fibres , pili, flagella, extracellular DNA  helps the uropathogen to form a niche that is protected from immune responses and antimicrobial compounds.⁴ Due to these reasons alternative therapeutic approaches for the treatment of  UTI are being explored for their ability to be potential drugs. Ethnobotanicals like Natural isothiocyanates (ITC), lemon grass (Cymbopogon citratus (DC), Arctostaphylos uva-ursi, Cranberry, Cinnamom verum J. Presl. (cinnamon), Ocimum gratissimum, L, and Mangifera indica, Zingiber officinale and Punica granatum, Ibicella lutea (Martyniaceae), Camellia sinensis, Ocimum suave, Cymbopogon citratus and Syzygium aromaticum, Coleus aromaticus and Ocimum sanctum, D-Mannose, Coccinia grandis, sage (Salvia officinalis L.), are found with antiuropathogenic activity against respective uropathogen causing urinary tract infection by the different researchers (Table 1).

Table 1: List of plants with anti-uropathogenic activity.

One such plant-based medication may be natural isothiocyanates (ITC). ⁵ The ITC originated from the plant horseradish (Armoraciae rusticanae radix) and nasturtium (Tropaeoli majoris herba). ITC antimicrobial activity against the selected isolates of uropathogenic E. coli is found very strong.⁵  ITC reduces UPEC internalization in human uroepithelial cell. But this effect is varied between the strains. This variation actually comes due to presence of virulence factor that are genetically determined but these genetic differences were not studied.⁵  Bioactive substances such as anthocyanins, flavonoids, terpenoids, catechins, and organic acids are abundant in cranberries.⁶ Hippuric acid quantity is found very high in urine on consumption of cranberry due to presence of quinic acid that make the urine acidic.⁷  Juice of cranberry is found vigorous barrier to the bacterial adherence.⁸ The anti-adhesive nature of cranberry is used as therapeutic agent against urinary tract infection. Additionally, it has been discovered that cranberries prevent type I and P-fimbriated uropathogens, mostly E. coli, from adhering to the uroepithelium.⁹

For the bladder infection one of potent herb named Arctostaphylos uva-ursi. Antibacterial activity is found against the UPEC due to presence of arbutin in the leaves of bearberry leaves.¹⁰ To test the antimicrobial activity against the uropathogen Proteus mirabilis, Klebsiella pneumonia, E. coli, and Pseudomonas aeruginosa, Enterobacteria, essential oils were isolated from three medicinal herbs: Salvia officinalis L., O. gratissimum L., and C. citratus (DC) Stapf. ¹¹ M.indica has many medicinal uses and its seed kernel ethanolic extract was found having antioxidant, antibacterial and antiviral property against the clinical isolates causing the urinary tract infection.¹² A potent antibacterial activity of Punica granatum and Zingiber officinale against E. coli is found in many research studies.¹³  In their study they tested acetone, ethanol and aqueous extract of these plants against the major clinical isolate of complicated urinary tract infection.

Ibicella lutea is America’s native plant and quasi carnivorous and its aerial parts extract is found  to have capacity to interfere the P. mirabilis growth, to check on biofilm formation capacity.¹⁴

Uropathogenic Escherichia coli (UPEC) that produce Extended Spectrum of Beta Lactamase (ESBL) and biofilm are both susceptible to the antibacterial activity of Coccinia grandis.¹⁵  Many infectious diseases are cured by traditional use of C. grandis, a medicinal plant existing in India. Coleus aromaticus and Ocimum sanctum essential oils also found with antibacterial activity against uropathogens causing urinary tract infection (UTI).¹⁶ Essential oils of Coleus aromaticus containing carvacrol as phytoconstituents found having more efficacy against the uropathogen in comparison with Ocimum sanctum containing eugenol and eugenol methyl ether as phytoconstituents. Syzygium aromaticum and Cymbopogon citratus oils are commonly employed in impoverished nations, especially India, to treat fungal infections of the mouth, skin, and vaginal tract because of their anti-biofilm properties against powerful strains of Candida albicans that form biofilms.^17] Green tea made from the Camellia sinensis leaves have polyphenolic catechins with strong beneficial component against UTI caused by E. coli. ¹⁸ Additionally, the essential oils isolated from Ocimum suave have antibacterial action against Citrobacter species, S. aureus, M. morganii, E. coli, P. aeruginosa, Enterobacter species, K. pneumoniae, and E. feacalis.¹⁹ In children receiving prophylactic treatment, the effectiveness and safety of cranberry products, such as cranberry capsules, are evaluated.²⁰ Urobactericidal potential in the P.granatum seed extract and Hemidesmus indicus root extract against Klebsiella pneumonia, E. coli, Staphylococcus aureus and Enterococcus faecalis strains isolated from UTI patient is also reported.^{21, 22, 23} Natural glycosides are found in the extract of herbal plants that help in prevention of UTI pathogenesis by hindering the adhesion of bacteria to host cell.

So, in our research we took isothiocyanate, Cyanidin, Quercetin, Limonene, Catechin, Carvacrol, Eugenol, oils, Polyphenolic Catechin and monoterpenes phytoconstituents of herbs which showed an uropathogenic activity in vitro to predict the druglikliness property. Then we also selected some random existing drug named Sulfamethoxazole, Nitrofurantoin, Fosfomycin, Fluroquinolones, and one potential chemical existing under review as antiviral, anticancer and also showing antibacterial property named Sunitinib as drug repurposing candidate to compare the pharmacokinetics  and druglikliness parameters against our phytoconstituents in order to find out the potentiality of our selected molecules to be drug molecules.

A significant role in the quick, low-cost approach, evaluation, and discovery of therapeutics is being achieved by computational methods. The application of a reliable and predictive data complement to experimental subjection can be  explored by computational method named SwissADME  in which ADME stands for (Absorption, Distribution, Metabolism, and Excretion)  that predict the pharmacokinetic, physicochemical, and pharmacological characteristics of small molecule in pharmaceuticals. This work sought to predict the biological activity of many phytochemical constituents of herbal medicines and then to compare them with existing drugs to find out their capacity to be potential therapeutics by computational analysis.

Materials and Methods

SwissADME

A free online program called SwissADME uses algorithms to determine a small molecule’s physicochemical characteristics, pharmacokinetics, and druglikeness. by BOILED-Egg (model to calculate the likelihood of a molecule to be absorbed by the gastrointestinal tract or permeate the blood-brain barrier ,five integrated models named  iLOGP , XLOGP3, WLOGP, MLOGP, SILICOS-IT to calculate molecule’s lipophilicity and Support vector machine (SVM) an algorithm to calculate if compound is likely to be a substrate or inhibitor. SwissADME require canonical SMILE information as input, so the first step is to visit the drug bank database (https://go.drugbank.com/) to retrieve chemical formula, structure and smile. The second step is to use SwissADME (http://www.swissadme.ch/). It provide output in ADMET (absorption, distribution, metabolism, and excretion) properties.²⁴

DruMAP

DruMAP is a web-based method that help in accessing the early drug discovery development.²⁵ It needs compounds smile in a file as an input for new prediction. In vitro parameters (metabolic stability, protein binding in plasma, protein binding in brain homogenate, and blood-to-plasma concentration ratio), in vivo parameters (drug amount in plasma and toxicity data), and numerous physiochemical parameters (solubility and distribution coefficient) are all accessible.^{26, 27}  DruMAP  obtain the pharmacokinetic and physicochemical parameters from ChEMBL database that  compiles information from experiments and reformat calculation in it.

Results

Table 2: Phytoconstituents of herbal medicine and existing Drugs

The physicochemical characteristics were then examined.

Table 3: Physicochemical properties

MW stands for molecular weight (g/mol); rotatable bonds (RB); hydrogen bond acceptor and donor (HBA and HBD); heavy and aromatic heavy atoms (HA and AHA, respectively); respectively; molar refractivity, or MR (m3/mol); Topology polar surface area (TPSA) (Ų) (Table 4 and 5): The phytoconstituents were then shown to have lipophilicity and water solubility properties.

Table 4: Lipophilicity characteristics

Table 5: Water solubility characteristics

Poorly < -6 < Moderately < -4 < Insoluble < -10 < Soluble < -2 Very < 0 < Highly
Then, using Lipinski’s principles, pharmacokinetic characteristics, bioavailability, and druglikeness were also assessed (Table 6 and 7).

Table 6: Bioavailability and pharmacokinetic characteristics

The terms “GI absorption” and “BBB permeant” refer to intestine and blood-brain barrier permeation, respectively.

Table 7: Score for druglikeness rules

MW < 500 Dalton; MR (molar refractivity should be between 40 and 130); H-bond donors – < 5; H-bond acceptors – < 10; Consensus Log P – high lipophilicity (written as LogP < 5); Overall.

Discussion

Table 3

The physicochemical properties include  molar refractivity, TPSA, sum total of heavy atoms, sum total of aromatic heavy atoms, sum total of rotatable bonds, sum total of H-bond acceptors, sum total of H-bond donors, molecular formula, and molecular weight. The PSA is calculated utilizing the polar atoms phosphorus and sulphur as well as a fragmental method called topological polar surface area (TPSA). The molecular weights of all the compounds were less than 500 Da, which is a critical requirement for compounds to be considered drug-like.

Table 4

We employed the SwissADME models XLOGP3, WLOGP, MLOGP, SILICOS-IT, and iLOGP to evaluate a molecule’s lipophilicity. XLOGP3, an atomistic method that incorporates a knowledge-based library and correction elements. MLOGP, the archetype of the topological technique, operates on a linear relation with 13 chemical attributes. SILICOS-IT is a method that employs 27 components and seven topological attributes. The physics-based iLOGP technique uses the generalized-born and solvent accessible surface area (GB/SA) model to calculate the solvation free energies in n-octanol and water. The log P o/w is the mathematical mean of the numbers predicted by the five suggested approaches.

Table 5

The water solubility properties  are displayed in Table 5. The most of compounds were soluble, moderately soluble and two were found highly soluble. The solubility of a substance is greatly influenced by the solvent employed, the ambient temperature, and the pressure. The point at which the solute’s concentration in the solution does not rise with the addition of more solute is known as the saturation concentration. The fractional logarithm of the molar solubility in water (log S) is used to calculate all predicted values. SwissADME further offers solubility in mol/l and mg/ml, as well as qualitative solubility classes.

Table 6

Pharmacokinetic characteristics and bioavailability  are displayed in Table 6. A large number of the compounds possess good GI absorption, that has a direct connection with the compound’s BBB. The accuracy of the model for GI passive absorption and prediction for brain access by passive diffusion to lay the BOILED-Egg (Brain or Intestinal L Estimate D permeation predictive model) was assessed using the Egan egg, an elliptical region occupied by well-absorbed molecules.

Table 7

The drug likeness rule score is displayed in Table 7. According to Lipisnki’s guidelines, constituent shown in table exhibited druglikeness. The Lipinski filter (Pfizer) is the first of five specifications that specifies small molecules through their physicochemical parameter profiles, comprising Molecular Weight (MW) < 500, MLOGP ≤ 4.15, N or O ≤ 10, and NH or OH ≤ 5.

Figure 1: Graphical information: here two fraction yellow shows the compound with probability to enter in brain and white shows the compound probability of absorption in GI tract.Click here to view Figure

Boiled Egg

The yellow region (yolk) on this graphical user interface indicates a high probability of brain penetration. A white area indicates that the gastrointestinal tract is likely to absorb it passively. There is no differentiation between the white and yolk regions. If a spot is determined to be a non-substrate of P-gp (PGP−), it is colored red; if it is determined that P-gp successfully releases it, it is colored blue (PGP+).

Fluroquinolone and Sunitinib are predicted to passively cross the blood-brain barrier (in the yolk) but pump out from the brain (blue dot), while polyphenolic catechin and cyanidin are predicted to be well-absorbed but not access the brain (in the white) and PGP+ (blue dot). It is expected that monoterpenes, limonene, carvacrol, eugenol, and allyl isothiocyanate will penetrate the brain (in the yolk) and not be released actively (red dot). It is anticipated that nitrofurantoin, quercetin, fosfomycin, and sulfamethoxazole will be effectively absorbed but not prone to active release. Since it is outside the plot’s range, one molecule oil should not be absorbed or BBB permeant.

Table 8: Dru Map prediction

Conclusion

Antimicrobial, antioxidant, anti-candida, anti-inflammatory and antibacterial are the potential biological activities of the phytoconstituents taken for the study.  The findings of the ADME research suggested that medicinal plant containing Allyl isothiocyanate, Cyanidin, Quercetin, Limonene, Catechin from cranberry, Carvacrol and  Eugenol from Coleus Aromaticus and Ocimum Sanctum, oils from Syzygium aromaticum  and Cymbopogon citratus, Polyphenolic Catechin from Camellia sinensis  and monoterpenes from Ocimum suave have the potential for drug development study. Dru MAP  results also confirms stability of compound calculated by Swiss ADME. Our research may serve as the foundation for further in vitro and in vivo research of Phyto drug from these phytoconstituents.

Acknowledgement

The authors are very grateful to amity university for providing opportunity to perform this study.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The authors do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration –

This research does not involve any clinical trials.

Permission to reproduce material from other sources

Not Applicable

Author Contributions

Nisha Mehlawat: Conceptualization, Methodology, Writing – Original Draft.

Jinny Tomar: Supervision,  Analysis, Review & Editing, final Approval.

Ravi Datta Sharma: Supervision,  Analysis, Review & Editing, final Approval.

Deepak Chand Sharma: Supervision,  Analysis.

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