In silico study of natural antioxidants.

Antioxidants are the body's defense system against the damage of reactive oxygen species, which are usually produced in the body through various physiological processes. There are various sources of these antioxidants such as endogenous antioxidants in the body and exogenous food sources. This chapter provides important information on methods used to investigate antioxidant activity and sources of plant antioxidants. Over the past two decades, numerous studies have demonstrated the importance of in silico research in the development of novel natural and synthesized antioxidants. In silico methods such as quantitative structure-activity relationships (QSAR), pharmacophore, docking, and virtual screenings are play critical roles in designing effective antioxidants that may be synthesized and tested later. This chapter introduces the available in silico approaches for different classes of antioxidants. Many successful applications of in silico methods in the development and design of novel antioxidants are thoroughly discussed. The QSAR, pharmacophore, molecular docking techniques, and virtual screenings process summarized here would help readers to find out the proper mechanism for the interaction between the free radicals and antioxidant compounds. Furthermore, this chapter focuses on introducing new QSAR models in combination with other in silico methods to predict antioxidants activity and design more active antioxidants. In silico studies are essential to explore largely unknown plant tissue, food sources for antioxidant synthesis, as well as saving time and money in such studies.

Inhibition activity prediction for a dataset of candidates' drug by combining fuzzy logic with MLR/ANN QSAR models.

A hybrid of artificial intelligence simple and low computational cost QSAR was used. Approximately 90 pyridinylimidazole-based drug candidates with a range of potencies against p38R MAP kinase were investigated. To obtain more flexibility and effective capability of handling and processing information about the real world, in this case, the fuzzy set theory was introduced into the QSAR. An integration of multiple linear regression and artificial neural network with adaptive neuro-fuzzy inference systems (ANFIS) was developed to predict the inhibition activity. The algorithm of ANFIS was applied to identify the suitable variables and then to find the optimal descriptors. The gradient descent with momentum backpropagation ANN was used to establish the nonlinear multivariate relationships between the chemical structural parameters and biological response. A comparison between the result of the proposed linear and nonlinear regression showed the superiority of QSAR modeling by ANFIS-ANN method over the MLR. The results demonstrated that the ANFIS could be applied successfully as a feature selection. The appearance of Diam, Homo, and LogP descriptors in the model showed the importance of the steric, electronic, and thermodynamic interactions between a drug and its target site in the distribution of a compound within a biosystem and its interaction with competing for binding sites.

Computer-aided drug design to explore cyclodextrin therapeutics and biomedical applications.

Cyclodextrin (CD) is a subset of the macrocyclic structural class, which is an important class of small organic agents that are useful functional excipients. They have wide range application possibilities in different fields of sciences such as material preparation, medicine, analytical chemistry, and separation processes. They are used widely in pharmaceutical formulations and drug delivery for increasing the water solubility of low soluble drugs and drug candidates. Due to the ring structure, they behave differently than smaller molecules and may be capable of hitting new classes of targets. A macrocyclic molecule presents varied functionality and stereochemical complexity in a pre-organized conformation of the ring structure. This can result in high selectivity and affinity for protein targets while conserving enough bioavailability to arrive at intracellular locations. Regardless of these valuable features, and the verified success of several marketed macrocycle drugs isolated from natural compounds, this class has been little explored in drug development. This study describes some of the key features of the CDs therapeutic discovery. Also, the application of computational chemistry approaches such as QSAR/QSPR, molecular docking, and molecular/quantum mechanics for modeling of CD-drug system is reviewed briefly.

Dual-acting of Hybrid Compounds - A New Dawn in the Discovery of Multi-target Drugs: Lead Generation Approaches.

Finding high quality beginning compounds is a critical job at the start of the lead generation stage for multi-target drug discovery (MTDD). Designing hybrid compounds as selective multitarget chemical entity is a challenge, opportunity, and new idea to better act against specific multiple targets. One hybrid molecule is formed by two (or more) pharmacophore group's participation. So, these new compounds often exhibit two or more activities going about as multi-target drugs (mtdrugs) and may have superior safety or efficacy. Application of integrating a range of information and sophisticated new in silico, bioinformatics, structural biology, pharmacogenomics methods may be useful to discover/design, and synthesis of the new hybrid molecules. In this regard, many rational and screening approaches have followed by medicinal chemists for the lead generation in MTDD. Here, we review some popular lead generation approaches that have been used for designing multiple ligands (DMLs). This paper focuses on dual- acting chemical entities that incorporate a part of two drugs or bioactive compounds to compose hybrid molecules. Also, it presents some of key concepts and limitations/strengths of lead generation methods by comparing combination framework method with screening approaches. Besides, a number of examples to represent applications of hybrid molecules in the drug discovery are included.

Computer Aided Drug Design for Multi-Target Drug Design: SAR /QSAR, Molecular Docking and Pharmacophore Methods.

Multi-target drugs against particular multiple targets get better protection, resistance profiles and curative influence by cooperative rules of a key beneficial target with resistance behavior and compensatory elements. Computational techniques can assist us in the efforts to design novel drugs (ligands) with a preferred bioactivity outline and alternative bioactive molecules at an early stage. A number of in silico methods have been explored extensively in order to facilitate the investigation of individual target agents and to propose a selective drug. A different, progressively more significant field which is used to predict the bioactivity of chemical compounds is the data mining method. Some of the previously mentioned methods have been investigated for multi-target drug design (MTDD) to find drug leads interact simultaneously with multiple targets. Several cheminformatics methods and structure-based approaches try to extract information from units working cooperatively in a biomolecular system to fulfill their task. To dominate the difficulties of the experimental specification of ligand-target structures, rational methods, namely molecular docking, SAR and QSAR are vital substitutes to obtain knowledge for each structure in atomic insight. These procedures are logically successful for the prediction of binding affinity and have shown promising potential in facilitating MTDD. Here, we review some of the important features of the multi-target therapeutics discoveries using the computational approach, highlighting the SAR, QSAR, docking and pharmacophore methods to discover interactions between drug-target that could be leveraged for curative benefits. A summary of each, followed by examples of its applications in drug design has been provided. Computational efficiency of each method has been represented according to its main strengths and limitations.

Application of Multivariate Linear and Nonlinear Calibration and Classification Methods in Drug Design.

Data manipulation and maximum efficient extraction of useful information need a range of searching, modeling, mathematical, and statistical approaches. Hence, an adequate multivariate characterization is the first necessary step in investigation and the results are interpreted after multivariate analysis. Multivariate data analysis is capable of not only large dataset management but also interpret them surely and rapidly. Application of chemometrics and cheminformatics methods may be useful for design and discovery of new drug compounds. In this review, we present a variety of information sources on chemometrics, which we consider useful in different fields of drug design. This review describes exploratory analysis (PCA), classification and multivariate calibration (PCR, PLS) methods to data analysis. It summarizes the main facts of linear and nonlinear multivariate data analysis in drug discovery and provides an introduction to manipulation of data in this field. It handles the fundamental aspects of basic concepts of multivariate methods, principles of projections (PCA and PLS) and introduces the popular modeling and classification techniques. Enough theory behind these methods, more particularly concerning the chemometrics tools is included for those with little experience in multivariate data analysis techniques such as PCA, PLS, SIMCA, etc. We describe each method by avoiding unnecessary equations, and details of calculation algorithms. It provides a synopsis of the method followed by cases of applications in drug design (i.e., QSAR) and some of the features for each method.

A quantitative structure property relationship for prediction of solubilization of hazardous compounds using GA-based MLR in CTAB micellar media.

QSPR studies for estimating the incorporation organic hazardous compounds in cationic surfactant (CTAB) were developed by application of the structural descriptors and multiple linear regression (MLR) method. Various structure-related descriptors were studied in order to derive information on hydrophobic, electronic and steric properties of solute molecules. Theoretical molecular descriptors selected by genetic algorithms-procedure were followed to predict logKs values by a stepwise-MLR method. A simple model with low standard errors and high correlation coefficients was selected. It was also found that MLR method could model the relationship between solubility and structural descriptors perfectly. The proposed methodology was validated using full cross validation and external validation using division of the available data set into training and test sets. The squared regression coefficient of prediction for the MLR model was 0.9624. The results illustrated that the linear techniques such as MLR combined with a successful variable selection procedure are capable to generate an efficient QSPR model for predicting the solubility of different compounds. The proposed model can be used adequately for the prediction and description of the solubility of organic compounds in micellar solutions.

Prediction of gas chromatography/electron capture detector retention times of chlorinated pesticides, herbicides, and organohalides by multivariate chemometrics methods.

A quantitative structure-retention relationship (QSRR) study, has been carried out on the gas chromatograph/electron capture detector (GC/ECD) system retention times (t(R)s) of 38 diverse chlorinated pesticides, herbicides, and organohalides by using molecular structural descriptors. Modeling of retention times of these compounds as a function of the theoretically derived descriptors was established by multiple linear regression (MLR) and partial least squares (PLS) regression. The stepwise regression using SPSS was used for the selection of the variables that resulted in the best-fitted models. Appropriate models with low standard errors and high correlation coefficients were obtained. Three types of molecular descriptors including electronic, steric and thermodynamic were used to develop a quantitative relationship between the retention times and structural properties. MLR and PLS analysis has been carried out to derive the best QSRR models. After variables selection, MLR and PLS methods used with leave-one-out cross validation for building the regression models. The predictive quality of the QSRR models were tested for an external prediction set of 12 compounds randomly chosen from 38 compounds. The PLS regression method was used to model the structure-retention relationships, more accurately. However, the results surprisingly showed more or less the same quality for MLR and PLS modeling according to squared regression coefficients R2 which were 0.951 and 0.948 for MLR and PLS, respectively.