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In Silico Analysis, Modeling, Docking and Pharmacophore Studies of Proteins Involved in Auto Immune Maladies (Rheumatoid Arthritis)

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In Silico Analysis, Modeling, Docking and Pharmacophore Studies of Proteins Involved in Auto Immune Maladies (Rheumatoid Arthritis) Sahithi, et al. Int J Pharm 2015; 5(3): 953-960 ISSN 2249-1848 International Journal of Pharmacy Journal Homepage: http://www.pharmascholars.com Research Article CODEN: IJPNL6 IN SILICO ANALYSIS, MODELING, DOCKING AND PHARMACOPHORE STUDIES OF PROTEINS INVOLVED IN AUTO IMMUNE MALADIES (RHEUMATOID ARTHRITIS) G. Prathima1*, Dr. A. Ravindernath2, Dr. P. Raja Rao 3, P. Sahithi 4 1*M.Tech Biotechnology Final year, University College of Technology, Osmania University, Hyderabad, India 2 Professor and Head, University College of Technology, Osmania University, Hyderabad, India 3 Associate Professor, University College of Technology, Osmania University, Hyderabad, India 4Assistant Professor, University College of Technology, Osmania University, Hyderabad, India *Corresponding author e-mail: [email protected] ABSTRACT Cytokine networks participate with paracrine and autocrine loops maintaining cellular activation in the synovial intimal lining. In rheumatoid arthritis inflammatory changes occur throughout the connective tissues of the body. The most useful medications in relieving the pain and disability of rheumatoid arthritis with anti-inflammatory properties are aspirin and ibuprofen. The present project was focused on study of anti-rheumatoid arthritis activity of bioactive compounds.In the present study, homology modeling, mutagenesis, docking studies were carried out with some of the selected bioactive compounds.PDB latest version was used to identify the target protein, obtain sequence from protein sequence data bank and homology modeling for the target protein was done using modeler 9.14 version and MOE 2008. version. Docking studies using molecular operating environment program revealed that Ellagic acid, Curcuminoid and Methyl gallate possess anti rheumatoid arthritis activity. Further, pharmacophore mapping studies were performed using DISCOVERY STUDIO on these compounds in order to identify the pharmacophoric feature responsible for the observed activity of the compounds. Keywords: Autoimmune disease, DISCOVERY STUDIO, Modeller, Pharmacophore, Rheumatoid Arthritis INTRODUCTION localized autoimmune diseases and systemic auto immune diseases. Hemolytic autoimmune disease is a Autoimmune diseases result from a dysfunction of clinical disorder due to destructions of blood the immune system in which the body attacks its own components where in auto Ab are formed against organs, tissues, and cells. Physicians and scientists one’s own RBCs, Platelets or Leucocytes. Examples have identified more than 80 clinically distinct include Hemolytic anaemia, Leucopenia, autoimmune diseases. Several are well known, Thrombocytopenia, etc. Localized autoimmune including rheumatoid arthritis, multiple sclerosis, diseases are also called as Organ specific type1 diabetes, and systemic lupus erythematosus; autoimmune diseases where a particular organ is others are less familiar, including autoimmune affected due to auto Abs. For example, Thyroiditis, hepatitis, autoimmune ear disease, and pemphigus. Multiple sclerosis, Type I DM. Systemic autoimmune The social and financial burdens imposed by these diseases are also called as Non-organ specific chronic, debilitating diseases include poor quality of autoimmune diseases where immune complexes life, high healthcare costs, and substantial loss of accumulate in many tissues and cause inflammation productivity. Auto immune diseases are broadly and damage. Examples include, Systemic Lupus classified into hemolytic autoimmune diseases, www.pharmascholars.com 953 Sahithi, et al. Int J Pharm 2015; 5(3): 953-960 ISSN 2249-1848 Erythematosus (anti-nuclear Ab.), Rheumatoid MATERIALS AND METHODS Arthritis (anti-IgG antibodies). Rheumatoid arthritis (RA), a chronic autoimmune Modeller: inflammatory disorder of unknown etiology occurs in Modeller 9.14 version is used in project for approximately 1% of the population [Albani and homology modeling of target protein. Modeller is a Carson 1997] where in it is more prevalent among computer program used in producing homology women than men, and usually develops in the fourth models of protein tertiary structures as well as and fifth decades of life with the primary presenting quaternary structures (rarer). It implements a symptoms being pain, stiffness and swelling of the technique inspired by nuclear magnetic resonance joints, accompanied by constitutional symptoms such known as satisfaction of spatial restraints, by which a as fever and malaise (Grassi et al. 1998)[1,2 ]. Synovial set of geometrical criteria are used to create a inflammation underlies the cardinal manifestations of probability density function for the location of each this disease, which include pain, swelling, and atom in the protein. The method relies on an input tenderness followed by cartilage destruction, bone sequence alignment between the target amino acid erosion, and subsequent joint deformities. Despite sequence to be modeled and a template protein whose intensive research, the precise cause of RA remains structure has been solved. The program also elusive. incorporates limited functionality for ab initio Cytokine networks participate with paracrine and structure prediction of loop regions of proteins, which autocrine loops that maintain cellular activation in the are often highly variable even among homologous synovial intimal lining. When cells are recruited to proteins and therefore difficult to predict by the synovium, or even perhaps at extrasynovial sites, homology modeling. The ModWeb comparative antigens can be processed by dendritic cells (DCs). protein structure modeling web server is based on They can present antigen in synovial germinal centers modeller and other tools for automatic protein or, more likely, migrate to central lymphoid organs, structure modeling, with an option to deposit the where they can activate naive T cells through resulting models into ModBase [5]. A new version of interactions with the T cell receptor (TCR) and EasyModeller (EasyModeller 4.0) has been recently costimulatory signals [3]. In rheumatoid arthritis released and available for free download for Linux inflammatory changes occur throughout the andWindows OS. There is also a simple interface to connective tissues of the body. The most useful modeller in the program UCSF Chimera. medications in relieving the pain and disability of rheumatoid arthritis are aspirin and ibuprofen, which Discovery studio: have anti-inflammatory properties as well and the DISCOVERY STUDIO is a suite of software for most useful drugs which slow down the disease simulating small molecule and macromolecule progression are Rheumatrex and Trexall. systems. It is developed and distributed by Bioinformatics is an interdisciplinary field that ACCELRYS. It helps to: combines computer science, statistics, mathematics, Investigate and test hypotheses in silico biological sciences and engineering to study and prior to costly experimental implementation, process biological data and develops methods and thus reducing the time and expense involved software tools for understanding biological data. It in bringing products to market. involves the development and application of data- Drive scientific exploration from target analytical and theoretical methods, mathematical identification to lead optimization with a modeling and computational simulation techniques to wealth of trusted life science modeling and the study of biological, behavioral, and simulation tools. socialsystems. Computational biology is different Leverage an open and scalable platform to from biological computation, which is a subfield of automate processes, create and deploy computer science and computer engineering using custom workflows, and integrate data types, bioengineering and biology to build computers, but is databases, and third-party or in-house tools. [4] similar to bioinformatics . Computational Biology, Enhance personal productivity and boost sometimes referred to as bioinformatics, is the team collaboration by enabling researchers science of using biological data to develop algorithms to share data and make better informed and relations among various biological systems. The decisions. tools and techniques employed in the present study are homology modelling, docking studies and The Molecular Operating Environment: pharmacophore studies. The Molecular Operating Environment, is a comprehensive software system for Life and Material Science developed by Chemical Computing Group 954 Sahithi, et al. Int J Pharm 2015; 5(3): 953-960 ISSN 2249-1848 Inc. (CCG). MOE is a combined Applications and other proteins, and even within pharmaceutical Environment and Methodology Development industry in structure-based drug discovery and drug Platform that integrates visualization, simulate ion design [7]. Homology modeling can provide the and application development in one package. MOE molecular biologists and biochemists with "low- strongly supports drug design through molecular resolution" structures, which will contain sufficient simulation, protein structure analysis, data processing information about the spatial arrangement of of small molecules, docking study of proteins and important residues in the protein and which may small molecules, and so on under the unified guide the design of new experiments. For example, operations. SVL, the Scientific Vector Language, is the design of site-directed mutagenesis experiments the portable high performance programming could be considerably improved if such "low- language built in MOE. SVL is the vectrized resolution"
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