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Chronic liver damage produces liver fibrosis. This disease leads to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Presently, hepatic fibrosis treated through only the withdrawal of the noxious agent. Therefore, there is an enormous scarcity of antifibrotic drugs. Therefore, drug developments through using potential new antifibrotic targets have been recently initiated. Several drug targets have been recorded which are leptin, leptin receptors, adiponectin etc. Here, we have chosen leptin receptors to develop the antifibrotic drugs. For that, we have developed 3D structure through homology modelling. We have also prepared a small molecular library with alkaloids (7 molecules) from East-Asian medicinal plants especially Indian, Chinese . Ultimately, we docked with these molecules with our drug target. Finally, it has been recorded that tetrandrine can bind with leptin receptor with less energy.
Keywords: hepatic fibrosis, drug target, leptin receptors, ligands
Hepatic fibrosis has been proved to be a life threatening complication of public, worldwide which occurs due to chronic liver injury which ultimately leads to cirrhosis of liver. The stimulus that triggers hepatic fibrosis includes viruses, autoimmune diseases, metabolic disorders and many more . In normal condition, only 5-10% of the cells of the liver are composed of hepatic stellate cells (HSC) that are present in the subendothelial space between hepatocytes and sinusoidal endothelial cells. These hepatic stellate cells (HSC) previously known as lipocytes, Ito cells, or perisinusoidal cells and were also recognized as the collagen-producing cells in the liver . This cell type was first explained by von Kupffer in 1876 which phenotypically activated during chronic liver diseases and causes fibrogenic properties . Under stressed condition induced by chronic or acute liver disease, HSC undergo phenotypic changes which will result in switching of these cells from a quiescent vitamin A rich phenotype to myofibroblastic phenotype [1,4]. De-novo fibrogenic properties are now shown by activated HSCs, which will include secretion of proinflamatory cytokines and chemokines, proliferation of the cells and synthesis of matrix proteins and inhibitors of matrix degrading protein in large excess [5,6], all of which will ultimately lead to progressive scar formation in the liver (Fig.1).
Till date, many approaches have been taken to inhibit or withdrawn the injurious agent that causes fibrosis; but this approach is not that feasible and hence efforts are directed for developing liver-specific antifibrotic therapies. There is no specific antifibrotic treatment has been detected yet, still continuous efforts are being enforced on clinical trials of evaluating small molecules that can pave the way for treating this deadly disease [8,9]. Moreover several experimental analyses have revealed that myofibroblastic activation of hepatic myofibroblasts derieved from portal connective tissue, perivascular fibroblasts of portal and central veins and periductular fibroblasts activates the hepatic satellite cells for inducing fibrosis. Rescent studies have focussed on emerging antifibrotic therapeutic targets which are- PPAR Î³ agonist (peroxisome proliferator activated receptor gamma agonist), leptin and leptin receptor, adiponectin etc .
Leptin and leptin receptor can be potential dug target for this disease . An obese gene is responsible for leptin synthesis and this protein derived from adipocytes cells whose work is to organize the food intake and energy equilibrium by using some kind of receptor (OB-R). Leptin serum levels are found to be increased in patients suffering from alcoholic cirrhosis of liver . It has been reported that mice with leptin deficiency or having mutations in leptin receptor showed reduced level of liver fibrogenesis . This protein is imperceptible in the normal liver which is produced during fibrogenesis can be by activated hepatic myofibroblasts in vitro and in vivo specially which is obtained by thioacetamide [11-12]. Therefore, any antagonists of leptin receptors can be promising drug candidate molecule hepatic fibrosis. So, leptin receptor blocking through antagonist has enormous potentiality to cure hepatic fibrosis.
Ligand molecules may act as an antagonist of receptor which has used as drug targets . Several medicinal plants which have been used for a long time are the source new candidate therapeutic molecules . Therefore, these medicinal plants which are the huge source of several compounds like flavonoid, terpenoid or other compounds may act as ligands . These plant derived ligands have shown its potentiality for the receptor inhibition . These plants may me less toxic; as, these plants have been used by the people for long time. Therefore, these plants especially medicinal plants have enormous potential for mining the ligand molecules.
In this study, we have developed drug candidate molecule for liver fibrogenesis through computer aided drug design. For that, we have chosen the leptin receptor to develop the antagonist for hepatic fibrosis. For ligand molecule, we have selected from some compounds of Chinese and Indian medicinal plants and prepared a small molecule library from East Asian medicinal plants especially form the medicinal Chinese and Indian medicinal plants. We have performed docking analysis small molecues with the leptin receptor. The binding energies from the docking analysis informed us that the tetrandrine can bind with leptin receptor with less energy.
METHODS AND MATERIALS
We have collected information about leptin receptor and this functional protein sequences in FASTA format was collected from the National Center for Biotechnology information (NCBI) (www.ncbi.nih.nlm.gov) and used for further analysis.
Preparation of the target protein by homology modelling
We have performed the homology modeling to generate the PDB structure. PDB structure of the leptin receptor is no available in the PDB database. The sequence of human leptin receptor (LEPR), called the target sequence, was used for homology modelling and the process of homology modelling of leptin receptor has been followed by method of Poornima et al. with some modification.
3D structure generation with PYMOL and generation of surface cavity and binding groove identification
The PyMOL, have been used to for the generation of 3D as well as identification of binding grooves of therapeutic targetsWe have used ".pdb" files to generate the surface structure and the cavities of those proteins.
Preparation of the compound library
PubChemÂ  is a publicly availableÂ databaseÂ ofÂ chemicalÂ moleculesÂ and their activities against biological assays. The system is maintained by theÂ National Center for Biotechnology InformationÂ (NCBI), a component of theÂ National Library of Medicine, which is part of the United StatesÂ National Institutes of Health(NIH). We have prepared a small molecular library of 7 compounds from East Asian medicinal plants especially form the medicinal Chinese and Indian medicinal plants retrieving the structures of the respective small molecules from pubchem.
Molecular docking has become an integral part of many modern structure-based drug discovery efforts. For docking, we have used the Hex  which is a fourier transform (FFT)-based protein docking server. Minimum energy with docked molecule was calculated using ligand information.
Surface Cavity and Binding Groove
Surface cavity and binding grooves has been provided in Fig.2. It has been recorded that The protein is having several surface cavity. However, five major surface cavities are noted.
We have also constructed molecular from East Asian medicinal plants especially form the medicinal Chinese and Indian medicinal plants library have been recoded in Table.1
Docking results with tetrandrine has been recoded in fig.3. and the docking parameters have been in table - 2. We have recorded that the binding energies from the docking analysis less for the tetrandrine which is -323.60 .
Here we have consider leptin receptor as drug target. Other people has describe that leptin receptor as drug target for heptic fibrosis . However PPAR Î³, adiponectin can also be used as drug target. the lPPAR Î³ are largely found in adipocytes cells and are responsible for adipogenesis. They are a member of nuclear receptor super family of ligand dependent transcription factors. During HSC activation, expression of PPAR Î³ decreases to almost undetectable level and re expressed when exposed to PPAR Î³ agonists [22-25]. Finally binding of PPAR Î³ with anti diabetic thioazelinediones decrease progression of fibrosis . However, it can be use a drug target. Alternatively, adiponectin, product of adipocyte cells, can be a drug target for lever fibroblasts. Several evidences have been obtained that supports the fact that during chronic liver diseases, adiponectin plays antifibrotic role .
Here, As, among the molecules tetrandrine binds with less energy with leptin receptor and it is for the artichoke,Â Cynara scolymus medicinal plant which has bee used by the people from long time. Therefore, we are hopeful that tetrandrine , may be a good drug candidate for future. However, more studies required in relation to the binding of the molecule with the leptin receptor.