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Cancer is a class of diseases characterized by out-of-control cell growth. Cancer is a leading cause of death worldwide. The p53 tumor suppressor (MDM2) is one of the principal mediators of cell-cycle arrest and the activation of apoptosis in response to cellular injuries. The aim of present study is designing a small molecule(antagonist) having capability to bind with the over expressed MDM2 protein and blocking its path to bind with p53 tumor suppressor protein that is having sufficient absorption and free of hepatotoxicity and carcinogenicity. A series of new lead analogs were designed on the basis of structure activity relationship properties then minimized and docked against protein which has the template 1YCR using online tools and software’s. Docking studies of lead molecule analogs designed by substituting different chemical groups shows good binding affinity towards active site of the protein. This studies may paves a new way for better treatment for cancer INTRODUCTION Cancer is the second leading cause of death in economically developed countries and the third in emergent nations.1 Although survival rates have increased due to efficient anticancer drugs and prevention, many types of cancer still have no effective cure. Cancer is an abnormal growth and proliferation of cells. It is a frightful disease because the patient suffers pain, disfigurement and loss of many physiological processes. Cancer may be uncontrollable and incurable, and may occur at any time at any age in any part of the body. It is caused by a complex, poorly understood interplay of genetic and environmental factors. 2-8 all cancers occur due to activation or mutation of oncogenes, or inactivation of suppressor genes. More than 20 tumor suppressor genes and 50 oncogenes have been identified and characterized. Most of these genes are involved in activation and detoxification of polycyclic aromatic hydrocarbons (PAHs), suggesting a potential role of these compounds in carcinogenesis. 9 The human p53 tumor suppressor protein has been one of the most investigated proteins in cancer research due to the fact that loss of p53 function through mutation and/or deregulation is involved in more than 50% of all human cancers. The role of p53 in controlling the cell cycle and monitoring the integrity of the genome has made it known as the “guardian of the genome”. P53 is tightly controlled in the non-stressed cell by its cellular antagonist MDM2 (murine double minute 2) through an auto regulatory feedback loop. Besides the functional loss of p53 through mutation, it can also be inactivated by the over expression or amplification of MDM2, which is the case in many tumors. Thus, disruption of the MDM2–p53 interaction is considered a novel therapeutic strategy for cancer cells that still are endowed with wild-type p53, and a variety of small molecule drug like compounds have been reported that bind to the p53 binding site of MDM2. EXPERIMENTAL SECTION Target Identification: Exact protein targets are identified only for a small fraction of biologically active compounds. Moreover, most small molecule compounds have multiple targets differentially expressed and interconnected in tissue -, cell type and disease specific manner. In life sciences research and drug discovery, target identification is a daunting task, which requires expertise in multiple fields, sophisticated experimentation, powerful knowledge resources, computational tools – and a lot of luck. The methods of Target identification extract useful knowledge from the raw data and help to focus on the relevant items of data. The most sophisticated aspect is the generation of new insights through the combination of information from different sources. Knowledge on the threedimensional structure (fold) of a protein provides clues on its function and aids in the search for inhibitors and other drugs. To retrieve and validate the MDM2 protein sequence using computational tools such as NCBI, UniProtKB, GeneCards, etc. The X-ray structure of unliganded human MDM2 with the p53 trans activation domain was used in the present study (PDB code: 1YCR). Active site Identification Active site of p53 protein was identified using CASTP server. 10 A new program, CAST, for automatically locating and measuring protein binding pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. When the search is complete, the largest site is automatically displayed on the structure. The results can be used to guide the protein–ligand docking experiment. Chemical Library: A chemical library or compound library is a collection of stored chemicals usually used ultimately in high throughput screening. The chemical library can consist in simple terms of a series of stored chemicals. Each chemical has associated information and its physiochemical properties with information such as the chemical structure, molecular formula, weight, logP, hydrogen bond donor, hydrogen bond acceptor, etc. characteristics of the compound. For this library of screening Accelyrs Discovery Studio, ChemSpider, PubChem, ChemBank, etc. databases were used. There are millions of compounds available in these databases. Through the help of these tools we can find a new compound against a melanoma cancer and tested for their ability to modify / inhibit the target protein. In compound screening the major part to test that compound is having druglkeness or must passed ADME properties. .We have used Accelyrs Discovery Studio for the present work. Molecular Modeling: If the structure of target or receptor protein is already available in protein structure database then no need to go for |
