Introduction to Drug Design & Discovery

Introduction to Drug Design & Discovery

• Drug design and discovery is a multi-faceted discipline involving aspects of biological, medical, and pharmaceutical sciences.
• Medicinal chemistry focuses on the discovery, design, identification, and preparation of biologically active compounds.
• It involves studying the mode of action of compounds at the molecular level, understanding relationships between structure and activity, and studying biotransformation.
• Medicinal chemists work in the pharmaceutical industry, designing and synthesizing new compounds for biological evaluation as potential drugs.

Medicinal Chemistry Introduction

• Medicinal chemistry is a chemistry-based discipline.
• It encompasses aspects of biological, medical, and pharmaceutical sciences.
• It focuses on the discovery, design, identification, and preparation of bioactive compounds.
• Medicinal chemists study the mode of action of compounds at a molecular level.
• They analyze structure-activity relationships and biotransformation processes.
• In the pharmaceutical industry, medicinal chemistry plays a key role in designing and synthesizing new compounds.
• A medicinal chemist is a competent organic chemist with good knowledge of biological sciences.

Fields of Study in Medicinal Chemistry

• The field includes invention, discovery, design, identification, and preparation of biologically active agents.
• Studying the metabolism of drugs is another key aspect.
• Interpretation of the mechanism of action of drugs is crucial.
• Establishing relationships between structural properties and activity is important.
• Predictive models help estimate the biological activity based on physicochemical parameters.
• Course objectives cover the prediction of biological response from chemical structure.
• Relating structural features to physicochemical properties is a key objective.
• Another goal is to predict the biochemical mechanism of action.
• Suggesting suitable analytical methodology is crucial.
• Utilizing enzyme or receptor models is important for relating chemical structure to activity.
• Predicting biological response from chemical alterations is another objective.

Drug

• A bioactive substance used in medicine to relieve, cure, or prevent diseases.
• Drug effects result from complex processes interacting with biological systems.
• A drug's action has three phases, which include pharmaceutical, pharmacokinetic, and pharmacodynamic processes.

Drug sources

• Drugs can be sourced from natural, semisynthetic, synthetic, and other sources.
• Natural drugs originate from minerals, animals, and plants.
• Mineral sources include substances like sodium bicarbonate and ferrous salts.
• Animal sources include hormones and vitamins from animals like fish liver oils.
• Plant sources contain alkaloids, cardiac glycosides, antibiotics, and anticancer drugs.
• Most modern drugs are synthetic, which have developed significantly in organic and organometallic synthesis.

Semisynthetic and Other Sources

• Semisynthetic drugs are intermediate between natural and synthetic agents and include fermentation products like antibiotics, amino acids, and vitamins.
• Other drug sources include microbial drugs, sera, and vaccines, with examples including the use of bacteria in complex natural compound production.
• The production of insulin using recombinant DNA technology is highlighted.

Drug Classification

• Drugs can be categorized based on their pharmacological effect (e.g., analgesics, antihypertensives).
• Chemical structures (e.g., quinolones, barbiturates) can be used for classification.
• Target systems like antihistamines and cholinergics are part of drug classification.
• Lead compounds (well-established substances with biological activity) play a crucial role in drug development.
• Accidental discoveries (serendipity) and observation of novel uses are frequently involved in the process of drug development.

Drug Discovery Methods

• Natural sources provide a significant source for drug discovery.
• Active compounds found in nature or their derivatives offer a source for new drugs.
• Random screening is a less effective method to discover drugs which involves testing numerous compounds in the hope of finding an active one.
• Rational drug design, a key approach to modern drug discovery, relies on understanding disease mechanisms.
• This allows for the targeting of specific biochemical processes leading to diseases.

Drug Discovery Process

• The drug discovery process involves several key steps, including strategic research, exploratory research, preclinical selection, and various clinical phases.
• Target identification and validation are crucial initial steps.
• Virtual screening and high-throughput screening are computational methods to identify potential hit candidates.
• Assay development is necessary to evaluate the effects of compounds on cellular processes.
• Hit-to-lead conversion involves identifying promising lead compounds.
• Lead optimization refines these molecules for desirable properties.
• Animal models evaluate efficacy and safety before human trials.
• Extensive human trials occur in phases I, II, and III before obtaining regulatory approval.

Drug Targets and Mechanisms of Drug Action

• Drug targets encompass enzymes, receptors, ion channels, and transporters.
• Drugs can act by reversibly or irreversibly inhibiting enzymes.
• Drugs interact with receptors to produce agonistic or antagonistic effects.
• Drugs can block or open ion channels.
• Drugs can inhibit endogenous substance uptake by transporters.

Definitions

• Ligands are molecules binding to biological macromolecules.
• Enzymes catalyze the conversion of substrates to products.
• Inhibitor molecules block the binding of the substrate to an enzyme, reducing its activity.
• Receptors are proteins, either membrane-bound or soluble, causing biological (intrinsic) effects after ligand binding.
• Agonists activate receptors, and antagonists block agonist action.
• Partial agonists have intrinsic activity, but generate a weaker response than full agonists.

Drug-Receptor Interaction

• Drug molecules interact with specific molecules (receptors) in biological systems to produce a response.
• Receptors are proteins and in some cases enzymes.
• Differences exist in the interaction mechanism between enzymes and other receptors
• The concept of ligand binding to receptors, and the resultant transduction of signals, are explained (e.g. cAMP synthesis)

Drug Classification

• Specific drugs work at extremely low concentrations and often select for particular tissues
• Slight modification in structure could alter the function of a specific drug and modify the result of interaction with a receptor from an agonist to an antagonist

Drug Receptors and Mechanisms

• All of high potency, biological selectivity, definite structural requirements, explain the presence of selective receptors.
• These receptors interact with endogenous mediators, controlling tissue functions and balanced well-being.
• Drug classification as agonists and antagonists, and their related attributes are described.
• The importance of occupancy theory, rate theory, and induced-fit theory to the concept of drug receptor interaction and drug activity.

Drug Discovery Process

• Various methods for drug discovery and the stages involve are outlined.
• The importance of serendipity and natural sources are highlighted
• Modern techniques like random screening, and rational drug design are discussed
• Understanding metabolism and retrometabolism are important, along with prodrugs.

Lead Modification Objectives

• The aim of lead structure modification is to improve drug properties like safety, potency, stability, selectivity, and duration.
• The essential organic groups for direct receptor interaction are identified (pharmacophore).

Lead Modification Approaches

• General strategies for structural modification, including disjunction/simplification, association/conjunction.
• Methods of modification - like changing the size and/or flexibility, and alteration of physicochemical characteristics.
• Specific approaches like molecular disjunction (simplification) involving the synthesis and evaluation of simple analogs as important approaches.
• Examples of lead modification, including disjunction techniques.

Molecular Association

• Several types of molecular associations for lead compound modification, such as molecular addition, replication, and hybridization.
• Examples to illustrate specific types of molecular association for lead compound modification, including ring opening, ring closer, and bulky group replacement.

Alteration of Physicochemical Properties

• Isosteric replacements involve substituting atoms or groups with similar properties and valences.
• Bioisosteres are molecules with similar size and shape, resulting in similar biological activity.
• Classifications of isosteres, including classic and nonclassical examples are described, with reference to therapeutic applications (such as antitumor drugs).
• Changing positions or orientations of specific groups can also be a method of modification, along with alterations in electronic properties. Examples concerning how changing the substituent group can change the half-life of the drug, as well as how structure-activity relationships affect the duration of action.

Retrometabolism Drug Design

• Retrometabolism drug design uses SAR and SMR concepts, involving a cyclical process of drug development.
• Different stages of the cycle or loop, with specific stages defined, and their relationship to target molecule.
• Classification of prodrugs, including their characteristics and types of prodrugs

Prodrugs

• A prodrug is a drug precursor that is inactive until metabolized in the body.
• Prodrugs can be classified based on their characteristics and method of action.
• Objectives for prodrug design, including water solubility, lipophilicity, longer duration of action, specific targeting, and improved patient acceptance.
• Examples regarding prodrug design and development (e.g. ampicillin, esters, examples of the various approaches to develop prodrugs)

Soft Drugs

• Soft drugs are actively metabolized to achieve their therapeutic effect.
• Soft drugs' metabolism is focused on a particular part of the molecule (soft spot) that controls the metabolism.
• This enables the tuning of the drug's metabolic fate to enhance efficacy and minimize unwanted side effects.

Examples of soft drugs

• Examples of soft drugs, including anti-inflammatory steroids and beta blockers, and how they illustrate the key concepts of soft drug design.

Explore the fascinating world of drug design and discovery through this quiz. Learn about the role of medicinal chemistry, the discovery and design of bioactive compounds, and the applications within the pharmaceutical industry. Test your understanding of the intricate relationships between chemical structure and biological activity.