Molecular Modeling Studies of Some Substituted 2-Phenyl-benzimidazole Derivatives as Inhibitors of IgE Response

We perform the two-dimensional (2D) QSAR studies of a series of substituted 2-phenyl-benzimidazole analogues to elucidate the structural properties required inhibitors of IgE response. The 2D-QSAR studies were performed using three statistical methods: the multiple linear regressions, giving square of correlation coefficient r2=0.8386, cross validated squared correlation coefficient q2=0.7218 and predictable ability pred_r2=0.7525; Multiple linear regression (MLR). The results show that the proposed 2D-QSAR models are valid and that they can be applied to predict the activities of substituted 2-phenyl-benzimidazole inhibitors of IgE response.


Introduction
Asthma is a chronic respiratory disease that affects 300 million adults and children worldwide, including 15.7 million adults and 6.5 million children in the United States [1]. The prevalence has increased by 50% in the past few decades, particularly in Westernized countries. Although corticosteroids and β2-agonists are effective in managing asthma symptoms, there is no curative therapy. There are also concerns regarding the side effects from chronic use of current drugs, particularly by children. The chronic nature of asthma and the lack of preventive and curative therapy are leading patients with asthma in Western societies to seek complementary and alternative medicine (CAM) treatment [2,3]. Human allergic disorders (type I hypersensitivity responses) ranging from hay fever, excema, and food allergies to potentially life threatening asthma and anaphylactic shock are increasing worldwide [4]. Central to the cascade of events that lead to these clinical allergic manifestations are protein-protein binding events between human immunoglobulin E (hIgE) and its class specific Fc receptors on effector cells [5][6][7]. Allergic asthma is a multifactorial disease, influenced by genetic and environmental factors, and is characterized by bronchial hyperresponsiveness, the presence of IgE antibodies to inhalant allergens and often also by enhanced total serum IgE levels. A switch recombination of antibodies to IgE requires two signals from activated T cells: the expression of the ligand for CD40 and the secretion of IL-4 or IL-13. Both IL-4 and IL-13, independently of each other, are able to induce IgE antibody [8][9][10]. The allergen-IgE interactions on the mast cell surface initiate a complex series of downstream signaling cascades, including phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) in the β-and γ-chains of FcεRI, resulting in mast cell degranulation [11,12]. While there are a number of pharmacological agents available for the treatment of asthma and allergic rhinitis, a major shortcoming of many of these therapeutic alternatives is that they impact the disease state by targeting a single mediator that modifies a response at the target organ. By acting on effecter molecules, these drugs provide some symptomatic relief but do not modulate the course of the disease. Anti-histamines, for example, continue to be the drugs of choice for allergic rhinitis because they are somewhat effective and are linked to few side effects [13].
QSAR refers to a discipline in computational chemistry that addresses the modeling of biological activities or chemical reactivity based on the quantitative description for the chemical structure of molecules. QSAR relies on the basic assumption that molecules with similar physicochemical properties or structures will have similar activities [14].
Quantitative structure activity relationship (QSAR) is one of the most important areas in chemometrics, and is a valuable tool that is used extensively in drug design and medicinal chemistry. Once a reliable QSAR model is established, we can predict the activities of molecules, and know which structural features play an important role in biological processes [15]. Since the QSAR model and properties of molecules can be obtained based on descriptors, choosing the most relevant descriptors is necessary. Therefore, using a technique as variable selection for extent number of descriptors is the most essential step in QSAR study [16]. The present paper deals with the novel development of drugs for the category, substituted 2-phenylbenzimidazole derivatives inhibitors of IgE response.
The main purpose of quantitative structure-activity relationship (QSAR) analyses is to make activity predictions for unknown compounds to guide the structure-based design of new analogues. Multiple linear regression (MLR) models have been developed as a mathematical equation which can relate chemical structure to the activity. The results obtained will be helpful to pharmacologists, chemists and medicinal chemists to come up with improved IgE responses drugs.

Materials and Method
A dataset of ninety four 2-phenyl-benzimidazole derivatives [17] (Richards et al.) for their IgE response have been taken for present QSAR work given in Table 1. Total of ninety four molecules were considered for this study out of which twenty four molecules were used as test set.
The test set was chosen so as to accommodate compounds with activities in a different range. QSAR models were developed for both the training and the test set molecules, and the test set was used to validate the developed models.
In logIC 50 values were converted to -logIC 50 in order to bring out better linear correlations and reduce clustering of compounds while generating QSAR regression lines. The experimental information associated with biological activity, which is used as dependent variables in building a QSAR model. In this study, computational work (2D-QSAR) was performed using Vlife MDS QSAR plus software [18] on a HP computer with Core2 Duo processor and a window XP operating system. 7 3  All the 2D descriptors were calculated for QSAR analysis using Vlife MDS 3.5 software. Energy minimization and geometry optimization were conducted using Merck molecular force field as force field and charge, maximum number of cycles were 1,000, convergence criterion (RMS gradient) was 0.01 and medium's dielectric constant of 1 by batch energy minimization method. The dataset of 94 molecules was divided into training set (71 compounds) and test set (23 compounds) by Sphere Exclusion (SE) method [19] for multiple linear regression (MLR) model with dissimilarity value of 11.2 using pEC50 activity field as dependent variable and various 2D descriptors as independent variables.
Energy-minimized geometry was used for calculation of descriptors, a total of 208 2D descriptors were calculated which encoded different aspects of molecular structure and consists of electronic, thermodynamic, spatial, and structural descriptors, e.g., retention index (chi), atomic valence connectivity index (chiV), path count, chain path count, cluster, path cluster, element count, estate number, semi-empirical, molecular weight, molecular refractivity, logP, and topological index.

Multiple linear regression (MLR)
MLR is a method used for modeling linear relationship between a dependent variable Y (pIC 50 ) and independent variable X (2D descriptors). MLR is based on least squares: the model is fit such that sum-of-squares of differences of observed and a predicted value is minimized. MLR estimates values of regression coefficients (r 2 ) by applying least squares curve fitting method. The model creates a relationship in the form of a straight line (linear) that best approximates all the individual data points. In regression analysis, conditional mean of dependant variable (pEC50) Y depends on (descriptors) X. MLR analysis extends this idea to include more than one independent variable. Regression equation takes the form Y=b1 * x1+b2 * x2+b3 * x3+c Where Y is dependent variable, 'b's are regression coefficients for corresponding 'x's (independent variable), 'c' is a regression constant or intercept [20,21].

Results and Discussion
For QSAR analysis regression was performed using pIC 50 values as dependent variables and calculated parameters as independent variables. In any thorough investigation of the effects of molecular properties, it is essential to prove that the results are both statistically valid. 2D-QSAR equations were selected by optimizing the statistical results generated along with variation of the descriptors in this model. Ntraining=71, Ntest=23, r 2 =0.8386, q 2 =0.7218, F test=43.3584, r 2 _se=0.1236, q 2 _ se=0.1733, pred_r 2 =0.7525, pred_r 2 se=0.4268.
In above QSAR models, r 2 is a correlation coefficient that has been multiplied by 100 gives explained variance in biological activity. Predictive ability of generated QSAR models was evaluated by q 2 employing LOO method. F value reflects ratio of variance explained by models and variance due to error in regression. High F value indicates that model is statistically significant. Eq. (1) shows 84 % variance in the observed activity values. The low standard error of r 2 _se=0.1236 demonstrates accuracy of the model.

Conclusion
A multiple linear regression (MLR) procedure was used to model the relationships between molecular descriptors and the inhibitors of IgE response of the benzimidazole derivatives. The quantitative structure-activity relationship (QSAR) analysis of some synthesized substituted 2-phenyl-benzimidazole derivatives inhibitors of IgE response were performed to find out the structural requirements of their IgE responses activities. Various 2D descriptors were calculated and used in the present analysis. The knowledge of Structure-Activity Relationship (SAR), together with the generation of QSAR, constitutes a large body of evidence that may assist in the development of new molecules with excellent biological activity and low toxicity. The results obtained from present investigation of IgE responses studies indicate that the presence of a chloropheny, fluoro-phenyl substituent leads to increase in the activity in comparison to the presence of a methyl group. QSAR analysis has been used to study the quantitative Citation: Sharma MC (2015) Molecular Modeling Studies of Some Substituted 2-Phenyl-benzimidazole Derivatives as Inhibitors of IgE effects of the molecular structure of the benzimidazoles on their inhibitory activity. In this model special emphasis was given to the contribution of electrotopological in predicting biological activity of 2phenyl-benzimidazole derivatives and they were found to improve the QSAR model and make it more precisely predictive.