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Article

Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach

1
Shreeyash Institute of Pharmaceutical Education and Research, Aurangabad 431136, India
2
Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1341, Bangladesh
3
Department of Pharmaceutical Chemistry, N.B.S. Institute of Pharmacy, Ausa 413520, India
4
Sub District Hospital Ambad, Jalna 431204, India
5
Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, India
6
Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
*
Authors to whom correspondence should be addressed.
Pathogens 2022, 11(11), 1296; https://doi.org/10.3390/pathogens11111296
Received: 22 September 2022 / Revised: 27 October 2022 / Accepted: 2 November 2022 / Published: 4 November 2022
(This article belongs to the Special Issue Infectious Diseases and Vaccine Technology Research)

Abstract

:
Cerebral malaria (CM) is a severe manifestation of parasite infection caused by Plasmodium species. In 2018, there were approximately 228 million malaria cases worldwide, resulting in about 405,000 deaths. Survivors of CM may live with lifelong post-CM consequences apart from an increased risk of childhood neurodisability. EphA2 receptors have been linked to several neurological disorders and have a vital role in the CM-associated breakdown of the blood–brain barrier. Molecular docking (MD) studies of phytochemicals from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, Ocimum basilicum, and the native ligand ephrin-A were conducted to identify the potential blockers of the EphA2 receptor. The software program Autodock Vina 1.1.2 in PyRx-Virtual Screening Tool and BIOVIA Discovery Studio visualizer was used for this MD study. The present work showed that blocking the EphA2 receptor by these phytochemicals prevents endothelial cell apoptosis by averting ephrin-A ligand-expressing CD8+ T cell bioadhesion. These phytochemicals showed excellent docking scores and binding affinity, demonstrating hydrogen bond, electrostatic, Pi-sigma, and pi alkyl hydrophobic binding interactions when compared with native ligands at the EphA2 receptor. The comparative MD study using two PDB IDs showed that isocolumbin, carnosol, luteolin, and taraxasterol have better binding affinities (viz. −9.3, −9.0, −9.5, and −9.2 kcal/mol, respectively). Ocimum basilicum phytochemicals showed a lower docking score but more binding interactions than native ligands at the EphA2 receptor for both PDB IDs. This suggests that these phytochemicals may serve as potential drug candidates in the management of CM. We consider that the present MD study provides leads in drug development by targeting the EphA2 receptor in managing CM. The approach is innovative because a role for EphA2 receptors in CM has never been highlighted.

1. Introduction

Cerebral malaria (CM) is a severe manifestation of a parasitic infection caused by the Plasmodium species. P. falciparum and P. vivax are the species responsible for most of the complicated forms of CM in humans. In 2018, there were an estimated approximately 228 million cases of malaria worldwide, resulting in about 405,000 deaths [1]. Approximately 20% of children admitted to the hospital with CM have died [2]. Of these, 67% were children under the age of 5 years [1,3]. Patients that survive CM have life-long post-CM consequences and an increased risk of developing neurological and cognitive deficits, behavioral difficulties, and epilepsy, therefore making CM a leading cause of childhood neurodisability [1,3,4]. Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) protein is synthesized during the parasite’s erythrocytic schizogony stage inside the RBC [5]. PfEMP1 acts as both an antigen and an adhesion protein [3]. PfEMP1 protein is then expressed on the RBC membrane. Receptors for this protein are also found in the endothelial cells of blood vessels and healthy RBCs [6,7]. Thus, the P. falciparum-infected RBCs (iRBCs) bind with the endothelial cells and healthy RBCs. There is an activation of immune response by the production of antibodies, which in turn leads to the release of inflammatory cytokines (LT-α and TNF-α), chemokines (CXCL10 and CCL2), ROS and RNS, all of which injure the brain tissues [8,9]. The binding of antibodies to PfEMP1 disables the binding properties of its DBL domains, thus resulting in a loss of cell adhesion, and the iRBC is destroyed; thereby, CM is prevented [9]. However, to escape the host’s immune response, different P. falciparum switch on and off different var genes to produce antigenically distinct PfEMP1s [6,7]. Each variant type of PfEMP1 has different binding properties and therefore is not recognized by the human immune system’s antibodies every time [3].
Disruption of the blood–brain barrier (BBB) is the key feature of CM, which may cause complications such as seizures and coma. Increased barrier permeability occurs due to structural disruption of adherence junctions present between the endothelial cells of the BBB [10,11]. It is clear that this barrier can be disrupted by two mechanisms: (a) apoptosis of endothelial cells and (b) opening of the tight junctions [11]. An experimental mouse model of cerebral malaria (ECM) has demonstrated that the T cells play a crucial role in the development of this condition [12]. Previous work suggests that cytotoxic T cells accumulate in the brain in response to inflammation induced by appropriated PfEMP1 protein iRBCs [12]. EphA2 receptors have been linked to several neurological disorders and have a major role in CM due to their association with the breakdown of BBB [13,14]. Here, we represent that EphA2 is a critical target protein facilitating the endothelial cell apoptosis process by targeting ephrin-A ligand-expressing CD8+ T cell adhesion [13]. This, along with the binding of soluble ephrin-A ligands, initiates signaling pathways, which in turn induces the opening of the tight junctions between the endothelial cells of the BBB. The purpose of the present work is to develop an adjunct therapy for CM based on blocking the EphA2 receptor. Analysis of the ephrin-A ligand’s soluble protein form and the form expressed on peripheral CD8+ T cells, both of which bind on the EphA2 receptor, has a strong correlation with the pathogenesis of CM. The crucial assumption is that EphA2 is upregulated on brain endothelial cells post-inflammation process, and it mediates the adhesion of ephrin-A ligand expressed CD8+ T cells, which in turn facilitates the process of degranulation and endothelial apoptosis [13]. EphA2-mediated signaling pathways will be triggered by the binding of CD8+ T cell-bound and the soluble form of ephrin-A ligands, and this will, in turn, mediate the opening of the tight junctions in the BBB [13]. The rationale for the present work is that the EphA2 receptor could serve as a novel target for the development of an adjunct therapy for CM. To date, there is no treatment protocol for CM that focuses on the EphA2 receptor as a target.
Molecular docking (MD) reveals various types of interactions of ligands with target EphA2 receptors, specifically via hydrogen and electrostatic bonds. The purpose of this research was to discover the chemical constituents from medicinal plants Taraxacum officinale (Dandelion), Tinospora cordifolia (Guduchi), Rosmarinus officinalis (Rosemary) and Ocimum basilicum (Basil) as potential blockers of EphA2 receptor through the MD study. Finding an effective therapy for CM is the need of the hour. Novel medicines/vaccines from sources apart from traditional or herbal remedies requires time-consuming clinical trials and long-term approval procedures. In contrast, we could develop a cure from traditional or herbal medicines relatively quickly [15]. Here, we have investigated some phytochemicals from these plants through an MD study to serve this purpose in managing CM.

2. Materials and Methods

2.1. Molecular Docking

To study the interactions between phytochemicals and the EphA2 receptor, MD experiments of phytochemicals derived from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, and Ocimum basilicum, together with the natural ligand ephrin-A, were conducted. The Autodock Vina 1.1.2 in PyRx-Virtual Screening Tool 0.8 software of the Chimera version 1.10.2 and the BIOVIA Discovery Studio Visualizer (version 19.1.0.18287) were used for the MD study [16]. All the docking poses, ligand, and protein interactions were studied by Discovery studio software which enables us to identify the types of interactions.

2.2. Ligand Preparation

In this study, the phytoconstituents of Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, Ocimum basilicum, and native ligand ephrin-A (SDF file) were obtained from the official website of the US National library of medicine PubChem (http://pubchem.ncbi.nlm.nih.gov/, accessed on 5 June 2022). Then, using the open babel tool, structures were imported into PyRx-Virtual Screening Tool 0.8 software, and the energy minimization process was performed by considering fundamental parameters based on the elements and their hybridization by a universal force field (UFF) [17]. The discovery studio software was employed for the prediction of the active sites of the selected EphA2 receptor.

2.3. Target Preparation

For the MD study, a three-dimensional grid box (size_x = 26.3786A°; size_y = 29.0004A°; size_z = 20.8096A°) was designed to define the area for interactions in the occupied cavity of EphA2receptor using Autodock tool 1.5.6 with exhaustiveness value of 8. The cavity was defined with the assistance of the Toggle Selection Spheres option that was provided in the Vina Wizard Tool of PyRx 0.8. This option was used to choose the active amino acid residues. The grid box was precisely positioned so that it could occupy all of the active binding sites as well as the critical residues. All the phytochemicals and EphA2 receptors were then subjected to docking to obtain the possible affinities/interactions with each other. The complete molecular docking procedure was performed as described by S. L. Khan et al. [17]. The complete molecular crystal structure of EphA2 Receptor Protein Kinase with PDB ID—6FNH and 5NK0 has been utilized MD study, which was developed by Kudlinzki D., Troester A. et al. (2018) and Kudlinzki D., Linhard V. L. et al. (2017).

3. Results and Discussion

3.1. Development of CM Associated with EphA2

The breakdown of the blood–brain barrier occurs during the blood stage of iRBCs in the schizont stage of Plasmodium infection. These iRBCs travel through the bloodstream and adhere to various receptors that are expressed on brain microvascular endothelial cells. These receptors include EPCR, ICAM-1, and other unknown receptors [5,6,13]. It has been demonstrated that ephrin-A ligand expression in the circulation (in soluble form as well as CD8+ T cell surface bound form) is elevated in P. falciparum-infected children with symptoms of CM (Figure 1) [13]. The approach is innovative because the role of EphA2 receptors in CM has not been highlighted until now. The present work is significant because the identification of new targets for adjunct therapies in CM is urgently needed.

3.2. Prediction of ADME Parameters

We have used the SwissADME (http://www.swissadme.ch, accessed on 10 June 2022) for the estimation of in silico ADME parameters of all our phytoconstituents. This provides insights into their pharmacokinetic behavior. To ensure drug-like properties, Lipinski’s rule of five is a prerequisite for rational drug design. All of the phytoconstituents under our study meet the criteria of Lipinski’s rule of five (mol. wt. ≤ 500 Da; log P o/w ≤ 5; HBD ≤ 5; HBA ≤ 10; Solubility (LogS): ≥ 4). It was found that all our phytoconstituents have the values of the ADME parameters in the requisite range, and hence, they possess drug-like characteristics as per Lipinski’s rule of five [18].
Estimation of the pharmacokinetic parameters of drug molecules enables researchers to predict some of their important biological aspects. In order to predict whether or not the compounds in question are optimum for oral bioavailability, Lipinski’s rule of five and Veber’s rules were utilized. All phytoconstituents were studied for their ADMET characteristics to assess their pharmacokinetic profiles and drug-likeness (Table 1).
We have investigated phytoconstituents from the Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, and Ocimum basilicum so as to identify the potential lead molecules through molecular docking study of their binding specificity in the target receptor cavity and binding free energies for the therapeutics management of CM. In compliance with Lipinski’s and Veber’s rules (Table 2), all of these phytoconstituents have demonstrated the characteristics of drug-like molecules, and also no violation of both of these rules by any phytoconstituent was observed (except taraxasterol, which violates one parameter viz., MLOGP > 4.15) [19]. All phytoconstituents have calculated log p values within the required range of the Lipinski rule of 5. The obtained values indicate good lipophilicity and high GI absorption along with access to the brain by crossing the BBB. Hence it is concluded that these phytoconstituents can probably be potential herbal lead compounds for the management of CM, especially in children. These phytoconstituents have an excellent binding affinity towards the EphA2 receptor, as predicted by the values obtained through molecular docking studies, and thus, they can act as EphA2 blockers. The Log p values of these phytoconstituents show the fair permeability of these drugs in the body to enter the target site in CM viz. the brain, and their capacity to bind with the EphA2 receptor. All these phytoconstituents were found to have the required values of mol. wt. ≤ 500 Da; log P o/w ≤ 5; HBD ≤ 5; HBA ≤ 10, and thus they have not violated the Lipinski rule of 5 (except taraxasterol). Additionally, these phytoconstituents have not violated the criterion as per Veber’s rule (viz. total polar surface area values, i.e., TPSA ≤ 140 and the number of rotatable bonds ≤ 10), and the values comply as they fall within the acceptable range for oral bioavailability [19].
It is concluded from the obtained values that the phytoconstituents under the present study show a good BBB penetration potential. Thus, they can be targeted for delivery to the central nervous system and may serve as potential lead compounds for the pharmacotherapy of CM. These phytoconstituents exhibit optimum log Kp (skin permeation, cm/s) and bioavailability scores and are readily permeated to the brain. All the phytoconstituents under study have values in the acceptable range of Ghose, Egan, and Muegge filters (Table 1). These phytocompounds display high lipophilicity and good GI absorption, and also they do not violate the Lipinski rule and Veber’s rule [18].

3.3. In Silico Toxicity Prediction Study Employing ProTox-II Toxicity Explorer

The in silico toxicity risk study of phytoconstituents using the open-source program ProTox-II toxicity explorer (https://tox-new.charite.de/protox_II/, accessed on 12 June 2022) (Table 3) was performed, which revealed that all our phytoconstituents were nontoxic [18]. Thus, they serve as promising leads for the therapeutic management of CM as adjuvant therapy in children. Some of the phytoconstituents viz., Methyl Chavicool, Palmatine, Magnoflorine, Carnosol, Rosmarinic Acid, Taraxasterol, and Taraxinic Acid show the biologic response of immunotoxicity. This actually might be helpful in the prevention of the neuroinflammatory immune response in the pathogenesis of CM, as neurodegeneration in CM is associated with the neuroinflammatory response which ultimately leads to the disruption of the BBB. As immunotoxicity for our phytoconstituents is predicted based on the structural database library in the software, it needs to be proved through pharmacological screening and toxicity study. It was also revealed that all of our phytoconstituents are inactive at the nuclear receptors, such as the Aromatase receptor, Androgen Receptor (AR), and Estrogen Receptor Alpha (ER). An exception to this generalization is the phytoconstituent Luteolin obtained from the Taraxacum officinale showed Estrogen Receptor Alpha (ER) active effects. ProTox-II also predicts LD50 values, and it was found that all of our phytoconstituents have significant LD50 scores, which indicates their safety and nontoxicity [18].

3.4. Docking Studies Using PyRx

EphA2 belongs to the family of tyrosine kinase receptors expressed mostly in hepatocytes, brain, and other tissues that plays important roles in tissue organization, homeostasis, and various pathological processes [20]. The ephA2 receptor is activated in response to binding with ephrin protein. EphA2 has a crucial role in CM associated with the breakdown of BBB integrity via neuroinflammatory responses, immune cell activation, platelets activation, and increased oxidative stress that all together leads to apoptosis of endothelial cells [9,11,12,13]. To prevent these episodes of CM, the plants under the present investigation have reported effects that can abolish such complications. A molecular docking study has shown that the blocking of the EphA2 receptor by phytochemicals from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, and Ocimum basilicum prevents endothelial cell apoptosis by averting ephrin-A ligand-expressing CD8+ T cell bioadhesion, as shown in Figure 2.
Taraxacum officinale has been used in traditional medicine in Europe, North America, and China. The phytochemicals of this plant have various biological activities such as hepatoprotective, anti-inflammatory, anti-diabetic, immune modulation, and anti-rheumatic [21,22]. Tinospora cordifolia is considered an essential herb in Ayurveda. It has pharmacologically proven effects such as antioxidant, antimicrobial, anti-malarial, antibacterial, and antifungal [23,24]. It is also utilized in treating hepatic and renal dysfunction [25]. Rosmarinus officinalis is considered one of the sacred plants to ancient Egyptians, Romans, and Greeks, and it has pharmacologically authenticated medicinal activities such as antioxidant, anti-inflammatory, hepatoprotective, antiulcer, anticancer, antiviral, antimicrobial, antiproliferative, improving cognitive deficits, neuroprotective and many more [26]. Rosmarinic acid has proven activities such as antioxidant, anti-inflammatory, control of hypercholesterolemia, oxidative stress and mental fatigue, and reduced lipid peroxidation in the heart and brain [27]. Similarly, antiangiogenic and neuroprotective effects are observed for carnosic acid (benzenediol abietane diterpene) and carnosol (phenolic diterpene) [28]. Essential oils from Ocimum basilicum have important therapeutic roles such as inflammatory, anticancer, antioxidant, stomachache, antimicrobial, antiviral, larvicidal and antileishmanial, and anti-aging [29]. They can prevent oxidative stress in these disease conditions and are thus used to treat cardiovascular diseases and jaundice [30]. Docking of phytochemicals from these plants on the EphA2 receptor with 6FNH and 5NK0 was performed, as reported in Table 4 and Table 5. All the phytochemicals were successfully docked on the EphA2 receptor having 6FNH and 5NK0. PubChem ID, molecular formula, molecular weight (gm/mol), binding affinity (kcal/mol), hydrogen bonds, and active amino acid residues for the said receptor are shown in Table 4 and Table 5. 3D and 2D images of docking poses showing the chemical structure of ligands and phytochemicals with the EphA2 receptor, which enables us to predict groups that evolve in interaction with EphA2, are shown in Figure 3 and Figure 4.
It is observed that all the phytochemicals of these plants have more binding affinity and interactions than the native ligands of both PDB IDs, except those of phytochemicals from Ocimum basilicum, as shown in Table 4 and Table 5 (Linalool, Methyl Eugenol, Methyl Chavicool). These phytochemicals from Ocimum basilicum have a lower molecular weight than that of native ligands, which might be the probable reason for their lower docking scores (binding affinity). Although these phytoconstituents demonstrate a lower docking score (binding affinity), they have greater binding interactions (viz. hydrogen bond, electrostatic, and Pi-sigma and pi alkyl hydrophobic bindings) as compared to the native ligand at the EphA2 receptor for both PDB IDs, as shown in Figure 3 and Figure 4. Luteolin and isocolumbin have shown better binding affinity values of −9.5 and −9.3 kcal/mol than the native ligand (PubChem ID: 134693866) on the EphA2 receptor (6FNH), respectively. Luteolin has shown more binding interactions with 6 hydrogen bonds with bond lengths 2.67, 2.26, 2.54, 2.22, 2.41, 3.54 A° with the active amino acid residues ASN744, THR692, GLU623, MET695, ASN744, respectively, as shown in Table 4 and Figure 3. It has also demonstrated 8 hydrophobic bonds with Pi-sigma and pi-alkyl type hydrophobic bonds with bond lengths 3.92, 5.35, 4.43, 4.74, 4.46, 5.49, 5.14, 4.51 A° showing the interactions with active amino acid residues VAL627, ILE619, ALA644, LEU746, ALA644, LX5646, LX5646, LEU746, ILE619, respectively. Isocolumbin shows less binding interactions and more binding affinity viz. −9.3 kcal/mol as compared to the native ligand (PubChem ID: 134693866). It demonstrates two hydrogen bonds having bond lengths 2.55 and 3.73 A° with GLN848 and PHE604, respectively, and one alkyl hydrophobic interaction with bond length 2.43 A° with ARG860 residue. The docking analysis has also shown that Taraxinic Acid (Dandelion) has a lesser binding affinity (−6.8 kcal/mol) and a single alkyl hydrophobic interaction having bond length 4.32 A° with LEU746 residue on EphA2 receptor (6FNH).
The docking study on the EphA2 receptor (5NK0) has shown that Taraxasterol and Isocolumbin showed the highest binding affinity (−9.2 and −9.0 kcal/mol) than native ligand (−7.6 kcal/mol) as shown in Table 4 and Figure 4 (PubChem ID: 127053578). Results from a docking study on EphA2 with 5NK0 have shown that Taraxinic Acid has more binding affinity (−8.7 kcal/mol) and increased binding interactions as compared to the molecular structure with 6FNH. Taraxinic Acid (5NK0) shows the 4-hydrogen bonding with bond lengths 2.45, 2.60, 2.98, 2.87 Aº with residues H-O, GLU696, LYS646, LYS646, and 5 hydrophobic interactions with bond length 4.34, 3.66, 4.24, 4.55, 5.24 with active amino acid residue VAL627, ALA644, LYS646, VAL627, ALA644 at the target receptor EphA2, as represented in Table 5 and Figure 4. The docking study on the EphA2 receptor (5NK0) reveals that Isocolumbin, Carnosol, Rosmarinic Acid, Carnosic Acid, and Taraxasterol have higher binding affinity values and lesser binding interactions as compared to the native ligand (PubChem ID: 127053578). MD study revealed that the blockade of EphA2 by phytochemicals from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, and Ocimum basilicum could prevent endothelial cell apoptosis by averting ephrin-A ligand-expressing CD8+ T cell bioadhesion.

4. Conclusions

EphA2 is identified as a new drug target in the host for the specific treatment of CM. Present in silico molecular docking study using phytochemicals of four plants under investigation viz., Taraxacum officinale, Tinospora cordifolia, and Rosmarinus officinalis have shown an encouraging result by blockade of the EphA2 receptor.
The present study has revealed that Palmatine, Magnoflorine, Isocolumbin, Carnosol, Rosmarinic Acid, and Carnosic Acid are the phytoconstituents from these plants that have a very good binding affinity score and favorable binding interactions with EphA2. The docking study of phytochemicals Isocolumbin, Carnosol, and Luteolin with EphA2 (6FNH) revealed the best binding affinity scores −9.3, −9.0, and −9.5 kcal/mol, respectively. While in the case of molecular docking with EphA2 (6FNH) phytochemicals Isocolumbin, Carnosol, Taraxasterol, and Luteolin have the highest binding affinity 8.2, 7.9, 9.2, and 9.0 kcal/mol, respectively. However, phytochemicals from Ocimum basilicum (basil) have a lesser binding affinity but undergo good binding interactions with the active residues of the EphA2 receptor. It is observed that Isocolumbin, Carnosol, Taraxasterol, and Luteolin have good binding affinities and target interactions, indicating the stability of the ligand receptor complex formed. This indicates that they are potential candidates to be used as a drug against CM.

Author Contributions

Conceptualization, M.S.S. and F.I.; methodology, M.S.S., F.I., S.L.K. and T.B.E.; software, P.P.G., R.R.G., and K.C.D.; validation, M.S.S., F.I., S.L.K., F.A.S., G.G.T., S.S.A., A.D. and T.B.E.; formal analysis, M.S.S., F.I., S.L.K., and T.B.E.; investigation, M.S.S., R.R.G., K.C.D., A.D. and T.B.E.; resources, M.S.S., F.I. and P.P.G.; data curation, M.S.S., R.R.G., S.L.K. and F.A.S.; writing—original draft preparation, M.S.S., F.I. and P.P.G.; writing—review and editing, M.S.S., F.I., P.P.G., K.C.D., S.L.K., F.A.S., G.G.T., S.S.A., A.D. and T.B.E.; visualization, M.S.S. and S.L.K.; supervision, M.S.S., S.L.K., and T.B.E.; project administration, M.S.S.; funding acquisition, T.B.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are thankful to the Principal, Shreeyash Institute of Pharmaceutical Education and Research, Aurangabad, Maharashtra, India, for providing research facilities to carry out this work.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. EphA2-associated cellular biochemical mechanism of development of CM. (1) iRBCs directed signaling through EPCR, ICAM-1, and UNK receptors lead to endothelial activation. (2) Release of various pro-inflammatory cytokines (LT-α and TNF-α and chemokine (CXCL10 and CCL2). (3) The cytokine LT-α can act on proximal endothelial cells to induce upregulation of the receptor EphA2. (4) TNF-α induces upregulation of ephrin-A1 ligand, which can be cleaved by metalloproteinases and is released into the bloodstream. (5) Chemokines such as CXCL10 and CCL2 recruit circulating immune cells, including CD8+ T cells, to the brain to the site of inflammation. (7) Ephrin-A1 ligand is then adhered to newly recruited CD8+ T cells and considered as ephrin-A1 ligand expressing CD8+ T cells. (7) Upon entry into the brain microvasculature, CD8+ T cells expressing the ephrin-A1 ligand bind to the EphA2 receptor expressed on brain endothelial cells leading to clustering and activation of EphA2. Forward signaling cascades from the EphA2 receptor led to the activation of the NF-κB pathway. (8) This results in various downstream consequences, including disruption of endothelial cell junctions due to both internalization and shedding of different adherents and tight junction protein components. (8) Once brain endothelial cell junctions are disrupted, contents of the vasculature can leak into the brain parenchyma. (9) This leads to vascular leakage, brain edema, and the development of other neurological symptoms associated with P. falciparum infection in CM (Modified diagram of Darling et al. 2020) [13].
Figure 1. EphA2-associated cellular biochemical mechanism of development of CM. (1) iRBCs directed signaling through EPCR, ICAM-1, and UNK receptors lead to endothelial activation. (2) Release of various pro-inflammatory cytokines (LT-α and TNF-α and chemokine (CXCL10 and CCL2). (3) The cytokine LT-α can act on proximal endothelial cells to induce upregulation of the receptor EphA2. (4) TNF-α induces upregulation of ephrin-A1 ligand, which can be cleaved by metalloproteinases and is released into the bloodstream. (5) Chemokines such as CXCL10 and CCL2 recruit circulating immune cells, including CD8+ T cells, to the brain to the site of inflammation. (7) Ephrin-A1 ligand is then adhered to newly recruited CD8+ T cells and considered as ephrin-A1 ligand expressing CD8+ T cells. (7) Upon entry into the brain microvasculature, CD8+ T cells expressing the ephrin-A1 ligand bind to the EphA2 receptor expressed on brain endothelial cells leading to clustering and activation of EphA2. Forward signaling cascades from the EphA2 receptor led to the activation of the NF-κB pathway. (8) This results in various downstream consequences, including disruption of endothelial cell junctions due to both internalization and shedding of different adherents and tight junction protein components. (8) Once brain endothelial cell junctions are disrupted, contents of the vasculature can leak into the brain parenchyma. (9) This leads to vascular leakage, brain edema, and the development of other neurological symptoms associated with P. falciparum infection in CM (Modified diagram of Darling et al. 2020) [13].
Pathogens 11 01296 g001
Figure 2. Pathogenesis of development and prevention of CM.
Figure 2. Pathogenesis of development and prevention of CM.
Pathogens 11 01296 g002
Figure 3. 2D and 3D docking poses of native ligand (a,f) and phytoconstituents [Methyl Eugenol (b,g); Palmatine (c,h); Carnosic Acid (d,i); Luteolin (e,j)] with Receptor-binding Domain (RBD) of EphA2 (PDB ID: 6FNH).
Figure 3. 2D and 3D docking poses of native ligand (a,f) and phytoconstituents [Methyl Eugenol (b,g); Palmatine (c,h); Carnosic Acid (d,i); Luteolin (e,j)] with Receptor-binding Domain (RBD) of EphA2 (PDB ID: 6FNH).
Pathogens 11 01296 g003aPathogens 11 01296 g003b
Figure 4. 2D and 3D docking poses of the native ligand (a,f) and phytochemicals [Methyl Eugenol (b,g); Palmatine (c,h); Carnosic Acid (d,i); Luteolin (e,j)] with Receptor-binding Domain (RBD) of EphA2 (PDB ID: 5NK0).
Figure 4. 2D and 3D docking poses of the native ligand (a,f) and phytochemicals [Methyl Eugenol (b,g); Palmatine (c,h); Carnosic Acid (d,i); Luteolin (e,j)] with Receptor-binding Domain (RBD) of EphA2 (PDB ID: 5NK0).
Pathogens 11 01296 g004aPathogens 11 01296 g004b
Table 1. Pharmacokinetic and drug-likeness properties of phytoconstituents.
Table 1. Pharmacokinetic and drug-likeness properties of phytoconstituents.
Sl. No.Parameter and Compound NameGI * AbsorptionBBB * PermeabilityP. gp* SubstrateCYP1A2 InhibitorCYP219 InhibitorCYP2C9 InhibitorCYP2D6 InhibitorCYP3A4 InhibitorLog Kp(Skin PermeationGhoseEganMueggeBioavailability
1LinaloolHighYesNoNoNoNoNoNo−5.13 cm/gm01 MW < 160Yes2 MW < 2000, heteroatoms < 20.55
2Methyl EugenolHighYesNoYesNoNoNoNo−5.60 cm/sYesYesNo0.55
3Methyl Chavicool (Basil)HighYesNoYesYesNoNoNo−5.34 cm/sYesYesYes0.55
4PalmatineHighYesYesYesNoNoYesYes−5.79 cm/sYesYesyes0.55
5MagnoflorineHighYesYesNoNoNoYesYes−6.44 cm/sYesYesyes0.55
6IsocolumbinHighNoYesNoNoNoNoNo−6.95 cm/sYesYesYes0.55
7CarnosolHighYesYesNoNoYesNoYes−5.01 cm/sYesYesYes0.55
8Rosmarinic AcidLowNoNoNoNoNoNoNo−6.82 cm/sYes1 TPSA > 131.6Yes0.58
9Carnosic AcidHighNoNoNoNoYesNoNo−4.86 cm/sYesYesYes0.56
10TaraxasterolLowNoNONONoNoNoNo−2.42 cm/s3 WLOGP > 5.6, MR > 130, atoms > 701 WLOGP > 5.882 XLOGP3 > 5, heteroatoms < 20.55
11
Luteolin (Dandelion)HighNoNoYesNoNoYesYes−6.25 cm/sYesYesYes0.55
12Taraxinic Acid (Dandelion)HighyesNONONoNONONo−6.89 cm/sYesYesYes0.85
* GI-gastrointestinal; BBB-blood–brain barrier; P-gp-p-glycoprotein.
Table 2. Molecular formula and drug-likeness properties of phytoconstituents.
Table 2. Molecular formula and drug-likeness properties of phytoconstituents.
Sr. No.CompoundsMolecular FormulaLipinski Rule of 5Veber’s Rule
Molecular WeightHBA *HBD *Log PViolationTotal Polar Surface Area (TPSA) (A2)Number of Rotatable Bonds
1Linalool (Basil)C10H18O154.25112.660020.234
2Methyl Eugenol (Basil)C11H14O2178.23202.580018.484
3Methyl Chavicool (Basil)C11H12O3192.21302.300035.534
4Palmatine (Guduchi)C21H22NO4+352.40402.530041.854
5Magnoflorine (Guduchi)C20H24NO4+342.41421.880062.162
6Isocolumbin (Guduchi)C20H22O6358.4612.130085.971
7Carnosol (Rosemary)C21H28O4344.44424.030066.761
8Rosmarinic Acid (Rosemary)C18H16O8360.31851.5200144.527
9Carnosic Acid (Rosemary)C20H28O4332.43433.820077.762
10Taraxasterol (dandelion)C30H50O426.72117.1101, MLOGP > 4.1520.230
11Luteolin (Dandelion)C15H10O6286.24641.7300111.131
12Taraxinic Acid (Dandelion)C15H18O4262.30412.120063.601
* HBA—Hydrogen bond acceptor; HBD—Hydrogen bond donor.
Table 3. Toxicity assessment and nuclear receptor signaling activation of marketed drug.
Table 3. Toxicity assessment and nuclear receptor signaling activation of marketed drug.
Sl. NoCompoundPredicted LD50 Value (mg/Kg)/Toxicity ClassHepatotoxicityCarcinogenicityImmunotoxicityCytotoxicityNuclear Receptor Signaling Pathways Active
Androgen Receptor (AR)Aromatase ActiveEstrogen Receptor Alpha (ER)
1Linalool (Basil)2200/5NoneNoneNoneNoneNoneNoneNone
2Methyl Eugenol (Basil)810/4NoneYesNoneNoneNoneNoneNone
3Methyl Chavicool (Basil)7900/6NoneNoneYesNoneNoneNoneNone
4Palmatine (Guduchi)200/3NoneNoneYesNoneNoneNoneNone
5Magnoflorine (Guduchi)401/4NoneNoneYesNoneNoneNoneNone
6Isocolumbin (Guduchi)280/3NoneNoneNoneNoneNoneNoneNone
7Carnosol (Rosemary)287/3NoneNoneYesNoneNoneNoneNone
8Rosmarinic Acid (Rosemary)5000/5NoneNoneYesNoneNoneNoneNone
9Carnosic Acid (Rosemary)287/3NoneNoneNoneNoneNoneNoneNone
10Taraxasterol (Dandelion)5000/5NoneNoneYesNoneNoneNoneNone
11Luteolin (Dandelion)3919/5NoneNoneNoneNoneNoneNoneYes
12Taraxinic Acid (Dandelion)900/4NoneNoneYesNoneNoneNoneNone
Table 4. MD study of phytoconstituents with EphA2 (PDB ID: 6FNH) representing the binding affinities (kcal/mol), hydrogen bonds, and active amino acid residues with their bond length (A°).
Table 4. MD study of phytoconstituents with EphA2 (PDB ID: 6FNH) representing the binding affinities (kcal/mol), hydrogen bonds, and active amino acid residues with their bond length (A°).
Sl. No.Compound NameMolecular Formula/Molecular Weight (gm/mol)Docking Score/Binding Affinity (kcal/mol)Active Amino Acid ResidueBond Length (A°)Bond CategoryBond Types
1Native Ligand (DXK) (PubChem ID: 134693866)C11 H10 N6/226.24−7.3GLU8152.17Hydrogen BondConventional Hydrogen Bond
ASP8412.65
GLU6262.28
ALA6503.94HydrophobicAlkyl
ALA6504.69Pi-Alkyl
TYR8135.27
2Linalool (Basil)C10H11O/154.25−4.9VAL6275.03HydrophobicAlkyl
LEU7464.81
MET6955.25
LEU7464.14
ALA6443.99
3Methyl Eugenol (Basil)C11H14O2/178.23−5.6GLU6263.40ElectrostaticPi-Anion
ALA6503.86HydrophobicAlkyl
PRO6874.01HydrophobicAlkyl
TRP8084.62HydrophobicPi-Alkyl
TYR8134.95HydrophobicPi-Alkyl
TRP8194.77HydrophobicPi-Alkyl
4Methyl Chavicool (Basil)C10H12O/148.20−5.4GLU8153.77Hydrogen BondCarbon Hydrogen Bond
GLU6263.53ElectrostaticPi-Anion
ALA6504.08HydrophobicAlkyl
PRO6874.10HydrophobicAlkyl
MET8405.46HydrophobicPi-Alkyl
TYR8135.04HydrophobicPi-Alkyl
TYR6285.41HydrophobicPi-Alkyl
5Palmatine (Guduchi)C21H22NO4+/352.4−8.4GLN8552.43Hydrogen BondConventional Hydrogen Bond
MET7335.02HydrophobicAlkyl
MET8514.26HydrophobicAlkyl
MET8515.21HydrophobicPi-Alkyl
PHE6044.57HydrophobicPi-Alkyl
6Magnoflorine (Guduchi)C20H24NO4+/342.4−7.9ASP7572.75Hydrogen BondConventional Hydrogen Bond
SER7562.00Hydrogen BondConventional Hydrogen Bond
LYS6464.63ElectrostaticPi-Cation
LYS6463.90HydrophobicPi-Sigma
MET6674.74HydrophobicAlkyl
ILE6763.64HydrophobicAlkyl
ALA6995.16HydrophobicPi-Alkyl
LEU7464.89HydrophobicPi-Alkyl
VAL6275.47HydrophobicPi-Alkyl
ALA6445.08HydrophobicPi-Alkyl
LEU7465.18HydrophobicPi-Alkyl
7Isocolumbin (Guduchi)C20H22O6/358.4−9.3GLN8482.55Hydrogen BondConventional Hydrogen Bond
PHE6043.73Hydrogen BondCarbon Hydrogen Bond
ARG8605.19HydrophobicAlkyl
8Carnosol (Rosemary)C20H26O4/330.40−9.0GLN6692.43Hydrogen BondConventional Hydrogen Bond
GLN8552.43Hydrogen BondConventional Hydrogen Bond
GLN8523.03Hydrogen BondConventional Hydrogen Bond
GLN8552.26Hydrogen BondConventional Hydrogen Bond
SER6713.57Hydrogen BondCarbon Hydrogen Bond
9Rosmarinic Acid (Rosemary)C18H16O8/360.3−7.6SER7562.54Hydrogen BondConventional Hydrogen Bond
TYR6943.25Hydrogen BondPi-Donor Hydrogen Bond
LYS6463.80HydrophobicPi-Sigma
N:UNK15.27HydrophobicPi-Pi Stacked
ALA6445.30HydrophobicPi-Alkyl
LEU7465.27HydrophobicPi-Alkyl
10Carnosic Acid (Rosemary)C20H28O4/332.4−7.3THR6052.20Hydrogen BondConventional Hydrogen Bond
LYS6032.35Hydrogen BondConventional Hydrogen Bond
GLN8482.58Hydrogen BondConventional Hydrogen Bond
PHE6043.06Hydrogen BondCarbon Hydrogen Bond
ILE8705.41HydrophobicAlkyl
11Taraxasterol (Dandelion)C30H50O/426.7−8.9ARG7433.66Hydrogen BondCarbon Hydrogen Bond
VAL6274.89HydrophobicAlkyl
ALA6444.40HydrophobicAlkyl
LEU7464.68HydrophobicAlkyl
12Luteolin (Dandelion)C21H20O11/448.4−9.5ASN7442.67Hydrogen BondConventional Hydrogen Bond
H-O2.26Hydrogen BondConventional Hydrogen Bond
THR6922.54Hydrogen BondConventional Hydrogen Bond
GLU6232.22Hydrogen BondConventional Hydrogen Bond
MET6952.41Hydrogen BondConventional Hydrogen Bond
ASN7443.54Hydrogen BondCarbon Hydrogen Bond
VAL6273.92HydrophobicPi-Sigma
ILE6195.35HydrophobicPi-Alkyl
ALA6444.43HydrophobicPi-Alkyl
LEU7464.74HydrophobicPi-Alkyl
ALA6444.46HydrophobicPi-Alkyl
LYS6465.49HydrophobicPi-Alkyl
LEU7465.14HydrophobicPi-Alkyl
ILE6194.51HydrophobicPi-Alkyl
13Taraxinic Acid (Dandelion)C21H28O9/424.4−6.8LEU7464.32HydrophobicAlkyl
Table 5. MD study of phytoconstituents with EphA2 (PDB ID: 5NK0) representing the binding affinities (kcal/mol), hydrogen bonds, and active amino acid residues with their bond length (A°).
Table 5. MD study of phytoconstituents with EphA2 (PDB ID: 5NK0) representing the binding affinities (kcal/mol), hydrogen bonds, and active amino acid residues with their bond length (A°).
Sl. No.Compound NameMolecular Formula/Molecular Weight (gm/mol)Docking Score/Binding Affinity (kcal/mol)Active Amino Acid ResidueBond Length (A°)Bond CategoryBond Types
1Native Ligand (91E) (PubChem ID: 127053578)C23H26ClN5O2S/472.00−7.6ASN7442.83Hydrogen BondConventional Hydrogen Bond
ASP7572.15
MET6952.15
THR6922.00
ARG7433.38Carbon Hydrogen Bond
TYR6945.54HydrophobicPi-Pi Stacked
ALA6995.03Pi-Alkyl
ILE6195.40
ALA6444.15
LEU7464.56
LYS6464.76
2Linalool (Basil)C10H11O/154.25−5.1LEU7464.78HydrophobicAlkyl
ILE6194.53
LEU7465.25
ALA6444.34
MET6955.26
LEU7464.38
ALA6444.01
LYS6274.44
VAL6274.03
ALA6444.88
TYR6944.97HydrophobicPi-Alkyl
3MethylEugenol (Basil)C11H14O2/178.23−5.2THR6922.44Hydrogen BondConventional Hydrogen Bond
GLU6633.73Carbon Hydrogen Bond
LEU7464.02HydrophobicAlkyl
MET6675.06
ALA6443.76
LYS6464.45
VAL6275.41Pi-Alkyl
ALA6445.07
LEU7465.22
4Methyl Chavicool (Basil)C10H12O/148.20−5.1LYS6464.49HydrophobicAlkyl
MET6675.15
ILE6903.73
VAL6275.23
LEU7464.45
VAL6274.76Pi-Alkyl
ALA6444.61
LYS6465.06
5Palmatine (Guduchi)C21H22NO4+/352.4−7.9THR6922.61Hydrogen BondConventional Hydrogen Bond
ALA6992.27
ILE6903.70Carbon Hydrogen Bond
LEU7463.57HydrophobicPi-Sigma
ALA6993.77Alkyl
ALA6444.02
LYS6464.30
LYS6464.57
MET6675.02
ILE6903.77
ALA6994.66Pi-Alkyl
6Magnoflorine (Guduchi)C20H24NO4+/342.4−7.8H-O1.90Hydrogen BondConventional Hydrogen Bond
ARG7433.76Carbon Hydrogen Bond
ASP7573.68
TYR6943.71
GLY6983.36
ILE6193.97HydrophobicPi-Sigma
ILE6193.98Alkyl
VAL6275.17Pi-Alkyl
LEU7465.28
ALA6444.63
LEU7464.58
TYR6944.89
7Isocolumbin (Guduchi)C20H22O6/358.4−8.2GLU6632.52Hydrogen BondConventional Hydrogen Bond
LYS6462.55
ILE6193.61HydrophobicPi-Sigma
8Carnosol (Rosemary)C20H26O4/330.40−7.9MET6672.82Hydrogen BondConventional Hydrogen Bond
LYS6465.21HydrophobicPi- Alkyl
9Rosmarinic Acid (Rosemary)C18H16O8/360.3−7.6ILE6902.12Hydrogen BondConventional Hydrogen Bond
ASP7573.81ElectrostaticPi-Anion
LEU7463.66HydrophobicPi-Sigma
ASP7573.93
LEU7465.15Pi-Alkyl
VAL6275.25
ALA6443.83
10Carnosic Acid (Rosemary)C20H28O4/332.4−7.7LEU7463.70HydrophobicPi-Sigma
LEU7464.73HydrophobicAlkyl
11Taraxasterol (Dandelion)C30H50O/426.7−9.2THR6922.01Hydrogen BondConventional Hydrogen Bond
VAL6274.80HydrophobicAlkyl
ALA6445.37
LYS6464.22
12Luteolin (Dandelion)C21H20O11/448.4−9H-O1.90Hydrogen BondConventional Hydrogen Bond
SER7562.18
LYS6462.82
THR6922.48
TYR6943.24Pi-Donor Hydrogen Bond
ILE6193.75HydrophobicPi-Sigma
LEU7463.63
VAL6275.04Pi-Alkyl
LEU7465.41
ALA6444.00
VAL6275.43
13Taraxinic Acid (Dandelion)C21H28O9/424.4−8.7H-O2.45Hydrogen BondConventional Hydrogen Bond
GLU6962.60
LYS6462.98
LYS6462.87
VAL6274.34HydrophobicAlkyl
ALA6443.66
LYS6464.24
VAL6274.55
ALA6445.24
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Shaikh, M.S.; Islam, F.; Gargote, P.P.; Gaikwad, R.R.; Dhupe, K.C.; Khan, S.L.; Siddiqui, F.A.; Tapadiya, G.G.; Ali, S.S.; Dey, A.; Emran, T.B. Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach. Pathogens 2022, 11, 1296. https://doi.org/10.3390/pathogens11111296

AMA Style

Shaikh MS, Islam F, Gargote PP, Gaikwad RR, Dhupe KC, Khan SL, Siddiqui FA, Tapadiya GG, Ali SS, Dey A, Emran TB. Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach. Pathogens. 2022; 11(11):1296. https://doi.org/10.3390/pathogens11111296

Chicago/Turabian Style

Shaikh, Mohd Sayeed, Fahadul Islam, Parag P. Gargote, Rutuja R. Gaikwad, Kalpana C. Dhupe, Sharuk L. Khan, Falak A. Siddiqui, Ganesh G. Tapadiya, Syed Sarfaraz Ali, Abhijit Dey, and Talha Bin Emran. 2022. "Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach" Pathogens 11, no. 11: 1296. https://doi.org/10.3390/pathogens11111296

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