Ocular Disorders

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The optics is the most invaluable organ of the human torso, which receive inputs from the external sources and feed the mind accordingly. Anatomically, the construction of the eye is not only complicated, rather difficult to consider the complicated anatomical structure of the retina, lens, cornea etc. (Trevor et al., 2007; Rafael, 2009).

Although there is a long list of ocular disorders, the prevalence differs from developing to developed nations. The incidences of disorders are more in the developing countries due to obvious reasons. As different all disorders such as uveitis, cataract, macular degeneration, diabetic retinopathy & Eales’ disease are major challenges for ophthalmologist, hence experimental and clinical studies are being carried out to understand the underlying mechanisms involved in etiopathogenesis of these disorders. Amongst these disorders, Eales’ disease is considered to be the most challenging one as it is most prevalent disease of young males (Das et al., 2010; Selvi et al., 2011; Biswas et al., 2013).

Eales’ disease is an idiopathic, inflammatory, venoocclusive disorder of the eye, which is predominantly characterized by recurrent vitreous haemorrhage induced inflammation with white haze layers around the outer coat of the venous blood vessels in the retina (Tiwari et al., 2010; Das et al., 2010; Irkec et al., 2012). It eventually leads to the sudden appearance of black spots in front of the eye or painless loss of vision. Eales’ disease most commonly affects healthy young adult males and is an important cause of preventable blindness in young adults. The predominant age of onset of symptoms is 20-30 years (Saxena et al., 2001). Eales’ disease is characterized by retinal periphlebitis, peripheral retinal ischemia, and haemorrhage. Eales’ disease is distinctively characterized both by stage of inflammation as well as the stage of proliferation (Ahmed et al., 2009; Lanzetta et al., 2012).

The key role of Retinal S-antigen and Interphotoreceptor retinoid binding protein-3 has been documented well in the etiopathogenesis of this disease (Biswas et al., 2013). This Retinal S-antigen protein has already been isolated and purified from whole retina as a soluble protein of 48-kD of rod outer segments. The purified protein shows specific binding to photo excited rhodopsin and found to involve in the quenching of light-induced guanosine 3′, 5′-monophosphate-phosphodiesterase activity (Saxena et al., 1999; Saxena et al., 2010).

In order to demonstrate the specific involvement of RSAG and RBP-3 in the pathogenesis of Eales' disease, the studies have been carried out for lymphocyte proliferative responses, uveitopathogenic peptides (peptide M and peptide G), yeast histone H3 peptide and uveitopathogenic fragments of Interphotoreceptor retinoid binding protein (IRBP; R16) (Rajasingh et al.,1996; Kyger et al.,2013).

The eye takes in several natural mechanisms to maintain itself against infection or injury. For example, tears keep the eye lubricated and physically clear away foreign particles such as dust or microorganisms. In addition, the tears contain several substances (e.g. Lysozymes and interferon) that protect against infection. The lids and eye lashes protect the ocular surface from the surroundings and help preserve the moist surface of the optic. Nevertheless, occasionally these defense mechanisms may be interrupted, resulting in ocular inflammation. Eye infections caused by exposure to bacterial, fungal, viral and other microbial agents are common and frequently reported in the all over the world. Plant materials are even being dictated by traditional healers and herbalist for the discussion of these disorders (Venkata et al., 2010; Sen et al., 2010; Sandhu et al., 2011; Pelkonen et al., 2014).

Herbs are staging a comeback and herbal ‘Renaissance’ is acceptable all over the globe. The herbal products today indicate safety in contrast to the synthetics that are stared as unsafe to human and environment. Although herbs had been priced for their medicinal, flavouring and aromatic qualities for centuries, the synthetic products of the modern age exceeded their importance, for a while. Nevertheless, the sightless reliance on synthetics is over and people are yielding to the naturals with hope of safety and protection. The traditional medicine all over the world is now days revalued by an extensive activity of research on different plant species and their therapeutic principles (Ayyanar, 2012; Gunjan et al., 2013; Bhatt et al., 2013). Observational evidence suggests that free radicals (FR) and reactive oxygen species (ROS) can be involved in a high number of diseases (Richards and Sharma, 1991; Lobo et al., 2010). As plants get a great deal of antioxidants to control the oxidative stress caused by sunbeams and oxygen, they can represent a source of novel compounds with antioxidant activity (Biswas et al., 2010; Singh et al., 2011; Subramanian et al., 2013).

Advances in computational research lead many significant contributions in the area of in silico characterization, molecular modeling, drug designing or herbal compound screening and many more. All major Pharma players in the world have established Bioinformatics Laboratories to fasten the discovery of novel lead molecules.

In silico characterization is important in deciphering the important physical and chemical properties along with the prediction of basic configuration of proteins in their secondary structure. These basic to advanced features of proteins can move over a leading idea about their structural and operative aspects. Physicochemical characterization of proteins give a better idea about the properties like molecular weight, atomic composition, isoelectric point, extinction coefficient, aliphatic index, GRAVY and instability index. All these parameters take a significant part in understanding the properties of protein under analysis. Prediction of secondary structure of protein is another important parameter in its morphological and operational analysis. Determination of various phosphorylation and signal peptidal cleavage sites help in exploring their functional aspects as phosphorylation and de-phosphorylation switches “on” and “off” the various bio-mechanisms in many enzymes and receptors (King et al.,2007; Shiva Kumar et al.,2007; Smith, 2009; Courtney et al.,2009; Tiwari et al.,2013).

The objective of computational protein structure prediction is to provide three dimensional (3D) structures with resolution comparable to experimental results. Comparative modeling, which predicts the 3D structure of a protein based on its sequence similarity to homologous structures, is the most precise computational method for structure prediction. 3D structure prediction may lead the various insights for advance studies in relation to virtual screening and docking (Liu et al., 2011; Mirjalili et al., 2013).

In the present investigations, studies were carried out to predict the structure of Retinol Binding Protein-3 and Retinal S-antigen using computational approaches along with the estimation of physicochemical parameters. Further, confirmation studies were also carried out to predict their active sites and virtual screening by following standard docking protocols. Docking is probably the best known methods employed to identify the binding between a receptor and a potential ligand. Predicting ligand-protein interactions are critical to success in many therapeutic research areas such as antibody modeling, elucidation of signal transduction pathways, and identification/ optimization of peptide or protein inhibitors or activators for drug discovery (Madhumathi et al., 2013). The natural ligands selected through literature search for this study were docked into the modelled 3D structures of Retinol binding protein-3 and Retinal S-antigen using AUTODOCK4.2. Gasteiger partial charges were added to the ligand atoms (Morris et al., 1998). Non-polar hydrogen atoms were merged and rotatable bonds were fixed. Docking calculations were carried out on the protein models (Gaba et al., 2010; Gutulla et al., 2011). Among the list of 60 selected herbal compounds or ligands, 10 was screened out on the ground of a literature search, having a major role in pro-ocular activities like anti-inflammatory, antioxidant, anti-haemorrhagic and many other activity. All the ligands were docked deeply with in the binding pocket region of Retinol binding protein-3 and Retinal S-antigen. Among these 10 compounds Ginkgolide exhibited the lowest binding energy which is representative of the highest potential binding affinity with the binding site of Retinol binding protein-3 and Retinal S-antigen. A good docking interaction implies the prediction of ligand conformation and orientation within the targeted binding site and their lower interactions energies. It could be predicted well from the docking results that during this course Ginkgolide would have found to be most effective and strongest binding ligand with Retinol binding protein-3 and Retinal S-antigen. This efficacy and suitability of ligand were determined on the basis of binding energy, RMSD, TPSA along with toxicity predictions. As Ginkgolide is showing minimum binding energy calculations, this was preferred as most suitable ligand against Eales’ disease for these selected proteins. Ginkgolide could have good molecular interactions with the receptors Retinol binding protein-3 and Retinol S-antigen; hence the use of this compound in inhibiting Retinol binding protein-3 and Retinol S antigen activity is implied for consideration in Eales’ related illness. In order to validate the in silico findings, in vitro experimentations were carried out in primary cultures of mice peritoneal macrophages by exposing to Ginkgolide. The results of in vitro studies were showing a significant linearity with in silico results obtained for Ginkgolide.

The working objectives of the study were-

  • Identification of proteins involved in genesis of disease.
  • Comparative modeling of identified protein.
  • Analysis of protein interaction with different natural and synthetic antioxidant and ligands.
  • Virtual screening by using available virtual library compounds.
  • In vitro screening of lead molecule to assess the possible therapeutic potential.