Understanding the Basics of QSAR for Applications in Pharmaceutical Sciences and Risk Assessment

Kunal Roy, Supratik Kar, Rudra Narayan Das

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780128016336
• Topic: Medicine
• Subtopic: Pharmacology

Understanding the Basics of QSAR for Applications in Pharmaceutical Sciences and Risk Assessment describes the historical evolution of quantitative structure-activity relationship (QSAR) approaches and their fundamental principles. This book includes clear, introductory coverage of the statistical methods applied in QSAR and new QSAR techniques, such as HQSAR and G-QSAR. Containing real-world examples that illustrate important methodologies, this book identifies QSAR as a valuable tool for many different applications, including drug discovery, predictive toxicology and risk assessment. Written in a straightforward and engaging manner, this is the ideal resource for all those looking for general and practical knowledge of QSAR methods.

• Includes numerous practical examples related to QSAR methods and applications
• Follows the Organization for Economic Co-operation and Development principles for QSAR model development
• Discusses related techniques such as structure-based design and the combination of structure- and ligand-based design tools

Chapter 1

Background of QSAR and Historical Developments

To search for the existence of any correlation among different objects or observations is a natural human tendency. The notion of quantitative structure–activity relationship (QSAR) modeling was evolved from the idea of possible existence of a mathematical correlation between the nature of chemicals and their behavioral manifestation. Following the initial observations, the “chemical nature” was conceptualized and explored in terms of information extractable from the structure and property of chemicals. Properties elicited by chemicals are significantly influenced by the nature of their chemical structure (branching, functional groups, electronegative behavior, stereochemical features, etc.), as well as different physicochemical properties (hydrophobicity, electronic nature, steric influence, etc.). The development of suitable descriptors (predictor variables) possessing a potential diagnostic nature in extracting the chemical attributes can help in exploring the mechanistic basis involved in a chemical–biological process following mathematical model development. Thus, QSAR studies allow a rational explanation for the behavioral manifestation of chemicals accompanied with providing knowledge on the mechanism involved, thereby creating an opportunity to tune the behavior of a chemical. As it provides a good alternative method to laboratory experimentation, at least for initial screening, QSAR is utilized in costly research like the design of drug molecules and assessment of chemical hazards. This chapter provides an account of the background, history, basic components, and application of QSAR techniques.

Keywords

quantitative structure–activity relationship (QSAR); descriptor; chemical attributes; modeling; chemical assessment

Contents

1.1 Introduction 2

1.2 Physicochemical Aspects of Biological Activity of Drugs and Chemicals 6

1.2.1 Hydrophobicity 6

1.2.2 Electronic effect 6

1.2.3 Steric effect 7

1.2.4 Forces and chemical bonding 7

1.2.4.1 Covalent bond 7

1.2.4.2 Ionic bond 8

1.2.4.3 Hydrogen bond 8

1.2.4.4 Hydrophobic force 10

1.2.4.5 van der Waals interaction 11

1.2.4.6 Pi–pi (π–π) stacking interaction 12

1.2.4.7 Charge transfer complex 14

1.2.4.8 Orbital-overlapping interaction 16

1.2.4.9 Ion-dipole and ion-induced dipole interaction 16

1.2.5 Structural features influencing response of chemicals 16

1.2.5.1 Stereochemical features influencing drug activity 17

1.2.5.2 Isosterism features influencing drug activity 17

1.2.5.3 Miscellaneous contribution of structural features 19

1.3 Structure–Activity Relationship 20

1.3.1 Ideology 20

1.3.2 The components and principal steps involved 23

1.3.3 Naming of the components 26

1.3.4 Objectives of QSAR model development 28

1.3.4.1 Prediction of activity/property/toxicity 28

1.3.4.2 Reduction and replacement of experimental (laboratory) animals 29

1.3.4.3 Virtual screening of library data 29

1.3.4.4 Diagnosis of mechanism 30

1.3.4.5 Classification of data 30

1.3.4.6 Optimization of leads 30

1.3.4.7 Refinement of synthetic targets 31

1.4 Historical Development of QSARs: A Journey of Knowledge Enrichment 31

1.5 Applications of QSAR 35

1.6 Regulatory Perspectives of QSAR 38

1.7 Overview and Conclusion 39

References 43

1.1 Introduction

Chemicals are essential components of human civilization. The applications of chemicals in the modern era span a wide range, from industrial to household environments. The esteemed goal of a chemist lies in the development of chemicals with the desired profile of their better behavioral manifestation; that is, activity/property. In cases of chemicals with pronounced biological activity or drugs, the chemist aims in enhancing the efficacy of the molecule while reducing any toxic effects exerted. Now, following the general axiom, development of a new chemical can be achieved either by designing a complete new entity or by modifying an existing one. In both cases, chemists need to possess sufficient knowledge regarding the nature of the chemical and its potential for interaction with the biological system. It is obvious that the biological activity (including toxicity) and property of any chemical (e.g., drugs, pharmaceuticals, and carcinogens) depend upon its interaction with the biological system concerned. Hence, the primary goal of a chemical designer lies in establishing a rational explanation of the mechanism of action of the chemical, which can lead to the derivation of a suitable theoretical basis and thus enabling the tailoring of its structure. Sometimes the lack of suitable explanation for a drug action limits the derivation of a hypothetical basis. In order to establish a proper theoretical basis for the action of chemicals, one would need to have a deep insight into the fundamental chemistry of the system that controls its physicochemical and structural behavior [1].

The biological activity elicited by chemicals is attributed by various interactions of the molecule at the critical reaction site in the biological system. The ligand molecule is recognized by a particular receptor followed by formation of a ligand–receptor complex involving different physicochemical forces. The complex then undergoes some conformational changes that lead to a series of events giving rise to the activity. The features possessed by a chemical entity get modified during its encounter with the biological system. Hence, elicitation of biological response is controlled by the way in which the chemical reacts at the active site of the biological system. In other words, the biological system plays a crucial role in determining the structural features of a chemical needed to elicit a desired response. Owing to the limited available space for this chapter, we shall not elaborate on this issue; instead, we would like to present a brief overview of the important steps and interactions involved at the biological reaction site when a chemical comes in contact with a biological system.

Before eliciting a desired response, drugs and other bioactive molecules are subjected to a complex path inside the biological system governed by their pharmacokinetic and pharmacodynamic behavior. Following administration, the drug molecules are subjected to the uncertainties arising from absorption, metabolism, excretion, and the random walk toward the critical reaction site, where it binds with a suitable receptor molecule. Figure 1.1 depicts different stages of pharmacokinetic movement of a drug inside the body. The random walk usually refers to the transportation of the drug molecule in various compartments, including the target site. The pharmacokinetic movements of the drug molecule, along with its pharmacodynamic properties, are regulated by a wide number of physical, chemical, and biological factors (e.g., partitioning behavior, solubility, pK_a value, ionization, interatomic distance, and stereochemical arrangement), and ultimately contribute to a considerable degree of complexity and uncertainty in some cases [2,3]. The drug molecules and other bioactive chemicals are considered to interact with macromolecular complexes present on the cellular surface or inside the cell to elicit a response. In the past, the response of several bioactive agents was considered to occur as a result of their interactions within a specific site of the living system. In the mid-1800s, Bernard [4] demonstrated that curare acts as a neuromuscular blocking agent by preventing the contraction of skeletal muscle following nerve stimulation, while its effect is lost when the muscle is subjected to direct stimulation. This study indicated the existence of chemical neurotransmission at the synapse between the nerve and muscle, and the curare was eliciting a localized response by cutting off the transmission. Later, Langley [5] provided further impetus to the concept of specific cellular component by showing the selective and potent action of parasympathomimetic agent pilocarpine which was selectively reversed by an atropine like compound. It was Ehrlich and Himmelweit [6] who introduced the term receptor or receptive substance in this re...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Foreword
• Preface
• Chapter 1. Background of QSAR and Historical Developments
• Chapter 2. Chemical Information and Descriptors
• Chapter 3. Classical QSAR
• Chapter 4. Topological QSAR
• Chapter 5. Computational Chemistry
• Chapter 6. Selected Statistical Methods in QSAR
• Chapter 7. Validation of QSAR Models
• Chapter 8. Introduction to 3D-QSAR
• Chapter 9. Newer QSAR Techniques
• Chapter 10. Other Related Techniques
• Chapter 11. SAR and QSAR in Drug Discovery and Chemical Design—Some Examples
• Chapter 12. Future Avenues
• Index