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International Journal of ChemTech Research CODEN( USA): IJCRGG ISSN : 0974-4290 Vol.2, No.3, pp 1808-1815, July-Sept 2010 Docking and QSAR studies of novel (E)-3-(4methanesulfonylphenyl)-2-(aryl) acrylic acids as dual inhibitors of cyclooxygenases and lipoxygenases Alireza Nematollahi*1, Asghar Davood1 1 Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. *Corres.author: alireza_nemat@yahoo.com Phone No: +98-21-22211361 Fax No: +98-21-88727330 Abstract: It is recently proposed that compounds with equal capabilities of inhibiting COX-II and 5-LOX, both are key enzymes involved in the arachidonic acid (AA) cascade, are expected to be safer non-steroidal anti-inflammatory drugs (NSAIDs). To dig out helpful information in designing dual functional inhibitors against the two enzymes, , molecular modeling, automated docking, and QSAR analyses were performed in this study on COX-2/5-LOX dual inhibitors, namely, (E)-3-(4-methanesulfonylphenyl)-2-(aryl)acrylic acids analogues. The structures were built by HYPERCHEM program and Conformational studies were performed through semi-empirical method followed by PM3 method. QSAR descriptors were obtained from the EDRAGON. QSAR equations were got from multi linear regression method. Docking study was performed by using autoDock4 program on the all compounds that have already been reported by Kanus et al. Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors. Therefore, the final QSAR models and the information of the inhibitor–enzyme interaction should be useful in developing new NSAIDs as anti-inflammation drugs with favorable safety profile. Keyword: acrylic acids, Molecular modeling, Docking, QSAR, COXII, 5-LOX. Introduction Two major enzyme families that include the lipoxygenases (5-LOX) and the cyclooxygenases (COX 2) metabolize arachidonic acid (AA). Proinflammatory leukotrienes (LTs) produced via the LOX pathway, and prostaglandins (PGs) produced via the COX pathway, are associated with adverse physiologic processes such as inflammation, fever, arthritis, bronchospasm [1] and the etiology of cancer.[2] Two of the three major isoforms (5-, 12and 15-LOX) observed in humans cause undesirable physiological effects. In this regard, 5-LOX is implicated in the production of LTs that are associated with inflammatory, bronchoconstrictor, hypersensitivity, anaphylactic and asthmatic actions.[1] and [3-4] Alternatively, PGs that induce undesirable inflammation, fever and pain are produced via the inducible COX-2 isozyme whereas PGs that regulate desirable gastrointestinal cytoprotective and renal functions are produced via the constitutive COX1 isozyme.[1] and [5].It is generally agreed that a dual inhibitor of the LOX/COX enzymatic pathways6 constitutes a rational concept for the design of more efficacious anti-inflammatory agents with an improved safety profile relative to ulcerogenic nonsteroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors that increase the incidence of adverse cardiovascular thrombotic effects.[67] and [8].Based on mentioned subject the computational studies on these compounds plays main role to rational design of dual inhibitors.The structures of desired compounds were built by using HYPERCHEM program. Conformations of the designed compounds were optimized through semiempirical method followed by PM3 calculation by using the HYPERCHEM software. Among all energy Alireza Nematollahi et al /Int.J. ChemTech Res.2010,2(3) minima conformers, the global minimum was selected. The crystal structure of COXII and 5-LOX were obtained from the Protein Data Bank (PDB) server .Then Docking calculations were carried out using Auto Dock program (Ver4) program. The QSAR descriptors were obtained from the EDRAGON. Finally, via a stepwise regression analysis, some main independent factors affecting the activity of the compounds were selected out, and then the QSAR equation was established. b) Molecular Modeling The chemical structures of inhibitors (table 1,2 ) were constructed using Hyperchem software (version 7, Hypercube Inc.) . Semi-empirical molecular orbital calculations (PM3) of the structure were performed 1809 Materials and Methods a) Data Set Our QSAR models will be computed based on the COXII and 5-LOX inhibitors activity, PIC50, for a set of six derivatives that were synthesized in pervious experiment by kanus et al. The general formula of the derivatives, their chemical structure, experimental PIC50 and calculated PIC50 values are presented in Table 1,2. using the Hyperchem program and the among all energy minima conformers (two favored tautomers), the global minimum of compounds were consider in docking calculations. Alireza Nematollahi et al /Int.J. ChemTech Res.2010,2(3) c) Docking Docking calculations were performed using Auto dock software (version 4). The models of COXII and 5LOX, (Fig1) that were generated by resorting to multi body molecular dynamics simulations were downloading from the PDB bank server (PDB entry 1T0J). Fig1_ COXII receptor (PDB entry: 6COX) Fig2_ 5-LOX receptor. 1810 In order to assign the perfect grid of each ligand, grid box values that were obtained by trial and error and previous study (Fig 2) .Finally docking was performed using the implemented Lamarckin GL and the default parameters and ten independent docking runs were performed for each DHPs. Alireza Nematollahi et al /Int.J. ChemTech Res.2010,2(3) d) Computation of Structural Descriptors and QSAR equations Quantitative structure activity relationships (QSAR) are widely used in the drug design process whenever detailed structural information on the ligand-receptor interactions are not experimentally available [9-11]. QSAR models are mathematical equations relating chemical structure to their biological activity [12-15]. The first component in the definition of a QSAR model is the computation of the structural descriptors from the three-dimensional molecular structure; various geometrical, quantum, or molecular field descriptors were proposed in recent years to replace the Hansch substituent constants [9-11],The second component in a QSAR model is an explicit mathematical structure-activity equation establishing a statistical relationship between a dependent variable (biological activity) and a set of independent variables (descriptors)[9-11].The mathematical QSAR equations can be computed with the help of a large number of statistical models, such as multi linear regression, partial least squares (PLS) [16-19]. For this study, many descriptors were calculated by the EDRAGON programs for all the compounds[19]. To 1811 select the set of descriptors that are most relevant to the IC50 of these agents, the MLR models were built and the QSAR equations with stepwise selection and elimination of variables were established by MLR method. Results Docking Flexible docking of all data sets used for the computational study was carried out on the active site of 5-LOX and COXII. The orientation of the most potent inhibitors, compounds 9e,9d , in the active site of COXII and 5-LOX respectively were examined by a docking experiment (Figure 3).[20] This molecular modeling shows the Oxygen of SO2 substituent forms a hydrogen bonding interaction with the OH of TYR385(distance=2.92) in 9e . The Hydrogen of OH forms hydrogen bond with the OH of GLU384 (distance=1.88) in 9d. The results of both receptors shown in table 3.These observations and experimental results provide a good explanation for the potent and selective inhibitory activity of these compounds. Fig3_ Docked structures of 9e(a), 9e (b) in Model of COXII, and Docked structures of 9d(c) in Model of 5-LOX. Fig 3(a) Alireza Nematollahi et al /Int.J. ChemTech Res.2010,2(3) Fig 3(b) Fig 3(c) 1812 Alireza Nematollahi et al /Int.J. ChemTech Res.2010,2(3) c) QSAR equation By using a stepwise multiple linear regression method, two QSAR equations were obtained as Follows for each part. In the QSAR equations, n is the number of data points, R2 is the correlation coefficient, S is the standard deviation, F is the Fisher’s F-value, , q2 is the LOO cross-validated coefficient, which was obtained by a multiple linear regression. yi is the actual activity ,y is the average actual activity, yi∧ is the predicted activity of compound i computed by the new regression equation. Large F, small S, very small p-value, as well as R2 and q2 values close to one indicate a good QSAR model. In general, the regression model is significant at pvalue