QSPR/QSAR Analyses by Means of the CORAL Software

In this chapter, the methodology of building up quantitative structure—property/activity relationships (QSPRs/QSARs)—by means of the CORAL software is described. The Monte Carlo method is the basis of this approach. Simplified Molecular Input-Line Entry System (SMILES) is used as the representation of the molecular structure. The conversion of SMILES into the molecular graph is available for QSPR/QSAR analysis using the CORAL software. The model for an endpoint is a mathematical function of the correlation weights for various features of the molecular structure. Hybrid models that are based on features extracted from both SMILES and a graph also can be built up by the CORAL software. The conceptually new ideas collected and revealed through the CORAL software are: (1) any QSPR/QSAR model is a random event; and (2) optimal descriptor can be a translator of eclectic information into an endpoint prediction.

Computational Techniques Application in Environmental Exposure Assessment

In this chapter, the application of computational techniques in environmental exposure assessment was described. The most important groups of these techniques are Multimedia Mass-balance (MM) modelling and Quantitative Structure-Activity/Structure-Property Relationships (QSAR/QSPR) modelling. Multimedia Mass-balance models have been widely utilized for studying Long-Range Transport Potential (LRTP) and overall persistence (POV) of Persistent Organic Pollutants (POPs), regulated by many national and international acts, including the Stockholm Convention on POPs. Recently, a novel modelling methodology that links QSPR and MM has been implemented. According to this approach, the physical/chemical properties required as the input variables for multimedia modelling can be calculated directly from appropriate QSPR models. QSPR models must be previously developed based on the relationships between the chemical structure and the modelled properties (QSPR).

QSAR Studies on Bacterial Efflux Pump Inhibitors

Antimicrobial drug resistance occurs when bacteria undergo certain modifications to eliminate the effectiveness of drugs, chemicals, or other agents designed to cure infections. To date, the burden of resistance has remained one of the major clinical concerns as it renders prolonged and complicated treatments, thereby increasing the medical costs with lengthier hospital stays. Of complex causes for bacterial resistance, there has been increasing evidence that proved the significant role of efflux pumps in antibiotic resistance. Coadministration of Efflux Pump Inhibitors (EPIs) with antibiotics has been considered one of the promising ways not only to improve the efficacy but also to extend the clinical utility of existing antibiotics. This chapter begins with outlining current knowledge about bacterial efflux pumps and drug designs applied in identification of their modulating compounds. Following, the chapter addresses and provides a discussion on Quantitative Structure-Activity Relationship (QSAR) analyses in search of novel and potent efflux pump inhibitors.

An Introduction to the Basic Concepts in QSAR-Aided Drug Design

The need for the development of new drugs to combat existing and newly identified conditions is unavoidable. One of the important tools used in the advanced drug development pipeline is computer-aided drug design. Traditionally, to find a drug many ligands were synthesized and evaluated for their effectiveness using suitable bioassays and if all other drug-likeness features were met, the candidate(s) would possibly reach the market. Although this approach is still in use in advanced format, computational methods are an indispensable component of modern drug development projects. One of the methods used from very early days of rationalizing the drug design approaches is Quantitative Structure-Activity Relationship (QSAR). This chapter overviews QSAR modeling steps by introducing molecular descriptors, mathematical model development for relating biological activities to molecular structures, and model validation. At the end, several successful cases where QSAR studies were used extensively are presented.

Quantitative Structure-Activity/Property/Toxicity Relationships through Conceptual Density Functional Theory-Based Reactivity Descriptors

Developing effective structure-activity/property/toxicity relationships (QSAR/QSPR/QSTR) is very helpful in predicting biological activity, property, and toxicity of a given set of molecules. Regular change in these properties with the structural alteration is the main reason to obtain QSAR/QSPR/QSTR models. The advancement in making different QSAR/QSPR/QSTR models to describe activity, property, and toxicity of various groups of molecules is reviewed in this chapter. The successful implementation of Conceptual Density Functional Theory (CDFT)-based global as well as local reactivity descriptors in modeling effective QSAR/QSPR/QSTR is highlighted.

Importance of Applicability Domain of QSAR Models

Quantitative Structure-Activity Relationship (QSAR) models have manifold applications in drug discovery, environmental fate modeling, risk assessment, and property prediction of chemicals and pharmaceuticals. One of the principles recommended by the Organization of Economic Co-operation and Development (OECD) for model validation requires defining the Applicability Domain (AD) for QSAR models, which allows one to estimate the uncertainty in the prediction of a compound based on how similar it is to the training compounds, which are used in the model development. The AD is a significant tool to build a reliable QSAR model, which is generally limited in use to query chemicals structurally similar to the training compounds. Thus, characterization of interpolation space is significant in defining the AD. An attempt is made in this chapter to address the important concepts and methodology of the AD as well as criteria for estimating AD through training set interpolation in the descriptor space.

The “ETA” Indices in QSAR/QSPR/QSTR Research

Descriptors are one of the most essential components of predictive Quantitative Structure-Activity/Property/Toxicity Relationship (QSAR/QSPR/QSTR) modeling analysis, as they encode chemical information of molecules in the form of quantitative numbers, which are used to develop mathematical correlation models. The quality of a predictive model not only depends on good modeling statistics, but also on the extraction of chemical features. A significant amount of research since the beginning of QSAR analysis paradigm has led to the introduction of a large number of predictor variables or descriptors. The Extended Topochemical Atom (ETA) indices, developed by the authors' group, successfully address the aspects of molecular topology, electronic information, and different types of bonded interactions, and have been extensively employed for the modeling of different types of activity/property and toxicity endpoints. This chapter provides explicit information regarding the basis, algorithm, and applicability of the ETA indices for a predictive modeling paradigm.

Quantitative Nanostructure-Activity Relationship Models for the Risk Assessment of NanoMaterials

In the last few decades, nanotechnology has been deeply established into human's everyday life with a great number of applications in cosmetics, textiles, electronics, optics, medicine, and many more. Although nanotechnology applications are rapidly increasing, the toxicity of some nanomaterials to living organisms and the environment still remains unknown and needs to be explored. The traditional toxicological evaluation of nanoparticles with the wide range of types, shapes, and sizes often involves expensive and time-consuming procedures. An efficient and cheap alternative is the development and application of predictive computational models using Quantitative Nanostructure-Activity Relationship (QNAR) methods. Towards this goal, researchers are mainly focused on the adverse effects of metal oxides and carbon nanotubes, but to date, QNAR studies are rare mainly because of the limited number of available organized datasets. In this chapter, recent studies for predictive QNAR models for the risk assessment of nanomaterials are reported and the perspectives of computational nanotoxicology that deeply relies on the intense collaboration between experimental and computational scientists are discussed.

QSAR-Based Studies of Nanomaterials in the Environment

Nanotechnology is a newly emerging field, posing substantial impacts on society, economy, and the environment. In recent years, the development of nanotechnology has led to the design and large-scale production of many new materials and devices with a vast range of applications. However, along with the benefits, the use of nanomaterials raises many questions and generates concerns due to the possible health-risks and environmental impacts. This chapter provides an overview of the Quantitative Structure-Activity Relationships (QSAR) studies performed so far towards predicting nanoparticles' environmental toxicity. Recent progresses on the application of these modeling studies are additionally pointed out. Special emphasis is given to the setup of a QSAR perturbation-based model for the assessment of ecotoxic effects of nanoparticles in diverse conditions. Finally, ongoing challenges that may lead to new and exciting directions for QSAR modeling are discussed.

QSAR Models towards Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease

Alzheimer's Disease (AD) is a multifactorial neurological syndrome with the combination of aging, genetic, and environmental factors triggering the pathological decline. Interestingly, the importance of the Acetylcholinesterase (AChE) enzyme has increased due to its involvement in the ß-amyloid peptide fibril formation during AD pathogenesis. In silico technique, QSAR has proven its usefulness in pharmaceutical research for the design/optimization of new chemical entities. Further, QSAR method advanced the scope of rational drug design and the search for the mechanism of drug action. It is a well-established fact that the chemical and pharmaceutical effects of a compound are closely related to its physico-chemical properties, which can be calculated by various methods from the compound structure. This chapter focuses on different Quantitative Structure-Activity Relationship (QSAR) studies carried out for a variety of cholinesterase inhibitors for the treatment of AD. These predictive models will be potentially used for further designing better and safer drugs against AD.