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Mechanistical Approach Through Discovery of New Generations Of ics om & B te i ro o P in f f o o r Hashemi et al., J Proteomics Bioinform 2011, 4:12 l m a Journal of a n t r i c u DOI: 10.4172/jpb.1000202 s o J ISSN: 0974-276X Proteomics & Bioinformatics Research Article OpenOpen Access Access Mechanistical Approach Through Discovery of New Generations of Anti Inflammatory Drugs Hashemi M1*, Borna H1, Dadras O1, Shafaroodi H1, Akbarzade A2 and Hajiali S1 1Islamic Azad University, pharmaceutical sciences Branch, Tehran, Iran 2Departments of Chemistry, IHU University, Tehran, Iran Abstract Non-Steroid-Anti-Inflammatory-Drugs (NSAIDs) are the main focal points of linkage between inflammation and cancer. These compounds affect the catalytic conversion of Arachidonic Acid to the main molecules of prostaglandin family. These exchanges are catalyzed by CycloOxygenase isozymes called COX I & II which are constitutive proteins in important organs like liver or kidney and inducible one in inflamed tissues or tumors, respectively. This study discusses on a new mechanistic approach through discovery of 4th generation of NSAIDs. Here utilizing combinations of online databases including DRUG BANK and PUBCHEM in conjunction with computational algorithms like Fast Flexible Docking as in FLEXX software followed by applying new filtering processes including extraction of structural descriptors by means of PASS software. Also, correlation between docking scores and bioactivities were analyzed by SPSS software. However, important molecular substructures were analyzed with Library MCS software for detailed constructional engineering of the compounds. All molecules and substructures were searched for their potential anti inflammatory activity in databases and searching engines such asISI , GOOGLE and etc. Consequently, new drug candidates were appeared in novel resources in order to synthesize, buy or extract for future in vitro assays. Keywords: Non-Steroid-Anti-Inflammatory-Drugs; PASS software; in order to reach new mother and lead compounds that are practically CycloOxygenase isozyme; FLEXX software accessible though chemical synthesis or natural extraction. We believe that this would be the nearest answer to problems of inflammations Introduction because every suitable and practical online softwares and databases are Drugs are of the most important concerns of human societies. utilized along with best approved computerized algorithmic softwares. Every year new drug generations are needed in order to cope with Materials and Methods new diseases and drug resistances. Among all diseases, cancer and inflammation are the most time consuming issues in world of science As any molecular bioinformatics project, a practical database is and health. However, inflammation is a severe or undesired human needed for future project steps. Our database is generated by addition body immune system response to foreign unfamiliar particles [1]. of all FDA approved NSAIDs downloaded from DRUG BANK These two are potentially different in mechanisms but similar in database to a library file. Then library file were docked by FlexX version some aspects. The main proteins which play a central role in both 3.1.4, BioSolveIt, software, uses Fast Flexible Docking Algorithm, with processes are CycloOxygenase (PGH2 Synthase) isozymes that COX I and COX II proteins. The crystallographic structures of these mediate conversion of Arachidonic acid to prostaglandin compounds. proteins were downloaded from PROTEIN DATA BANK (PDB) as Arachidonic acid is oxidized and peroxidized to PGG2 and PGH2 1U67 and 1PXX. Interaction energies were derived for both proteins respectively [2]. The active site of this enzyme consists of a long channel and subtracted COX II from COX I in order to gain the highest energy coated with hydrophobic residues that ends with Tyr 385 and Ser 530 differences. Then top molecules with highest energy differences were which could be affected by some of NSAIDs during inhibition [3]. COX selected and searched for their similarities in PUBCHEM databases I is a constitutive protein that is apparently expressed in all important with 90% threshold. On the other hand, top structurally different human tissues such as brain, liver, kidney, stomach and etc and protects molecules were sub-structurally searched in mentioned databases too. them from shocks and stresses. On the other hand, COX II only Then similar molecules were filtered by virtual screening mechanisms expresses in stressed tissues, inflamed organs and tumors to enhance to decrease the likeliness between similar molecules and compounds blood circulations or improved immune responses [4]. Inhibition of with drug specifications. At the next phase these molecules were docked COX II not only stops mentioned processes but also affects COX I with both proteins yet again for better screening of affecting molecules expressed organs and harms them. Various ranges of compounds could affect inflammation states such as steroids or cytokines [5]. The main compounds used to suppress COX II catalytic activity are called Non *Corresponding author: Hashemi M, Islamic Azad University, pharmaceutical sciences Branch, Tehran, Iran, E-mail: [email protected] Steroid Anti Inflammatory Drugs (NSAIDs). These molecules directly interact with active site of enzyme and inhibit them from enzymatic Received July 30, 2011; Accepted December 10, 2011; Published December 13, 2011 reactions [3]. There have been there generations of NSAIDs till now Citation: Hashemi M, Borna H, Dadras O, Shafaroodi H, Akbarzade A, et al. (2011) that could be used in treatments of inflammations. Aspirin, diclofenac Mechanistical Approach Through Discovery of New Generations of Anti Inflammatory and gelophen are belonged to first, second and third generations, Drugs. J Proteomics Bioinform 4: 284-288. doi:10.4172/jpb.1000202 respectively [6]. This study discusses about possible new generation of Copyright: © 2011 Hashemi M, et al. This is an open-access article distributed NSAIDs which more specifically tend to inhibit COX II rather than under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the COX I. Here some mechanistic bioinformatics approaches are applied original author and source are credited. J Proteomics Bioinform ISSN:0974-276X JPB, an open access journal Volume 4(12) : 284-288 (2011) - 284 Citation: Hashemi M, Borna H, Dadras O, Shafaroodi H, Akbarzade A, et al. (2011) Mechanistical Approach Through Discovery of New Generations of Anti Inflammatory Drugs. J Proteomics Bioinform 4: 284-288. doi:10.4172/jpb.1000202 in order to enhance COX II specificity. Similar filtered molecules specifies the focal screening step of new anti inflammatory compounds. were studied for their availability in natural resources in databases Bioactivity filtering was performed by applying PASS software for and references. At the second phase all NSAIDs were analyzed for structure and activity relationship prediction of all concluding their main comprising fundamental and organic functional groups molecules. Compounds with higher than 60% anti inflammatory along with second generation similar molecules by Library version activity were selected for final literature searches and analyzes. Figure 0.7, ChemAxon software series to recognize most affecting groups in 3 shows the platform of PASS software with anti inflammatory analysis ligand-protein interactions. IUPAC names were generated for these of a similar molecule. organic functional groups by ACD lab/ChemSketch version 11.01, Advanced Chemistry Development Group. More guaranteeing the Some top rated molecules of different sources are represented activities of similar molecules PASS software, V.poroikov et al, version in Table 2 along with their docking scores and bioactivities. 1.917, was utilized to predict their anti inflammatory tendencies. Cyclooxygenase Inhibitory and Anti Inflammatory bioactivities of all Filtered molecules were literately searched for their and derivatives gathered compounds were analyzed for more precision in molecule presence at natural resources in books, databases and websites such selection. However, these predictions could be accomplished in as Flore of Iranica, ILVIS and CHCD and ISI, GOOGLE and Science Enhanced NCI database too [7]. In addition, drug likenesses were Direct, respectively. On the other hand the relationships of docking driven by PASS software in order to decrease cytotoxicity of elected scores and predicted activities were studied for their rationality. compounds [8]. About 1000 molecules gathered and looked for their Results availability in natural resources such as plants or aquatic animals. About 53 molecules were gathered from DRUG BANK databank It is obvious that best predicted molecules have high docking and all combined in a library file in order to dock with proteins by scores compared with their source molecules. Graph 1(included as FlexX software. Figure 1 demonstrates the workbench of FlexX with supplementary data), represents docking scores of selected molecules COX I active site which is designed as docking site for all ligand types. with COX II in detail. Table 1 shows interaction energies of both proteins and their Also functional groups were explored by their generated names subtractions. The highest differences between IEs are highlighted in for any possible anti inflammatory activity in any compound. These table. Top 10 molecules were selected to progress the project. searches accomplished in ISI and Science Direct databases,
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