Introduction to Drug Design & Discovery

Introduction to Drug Design & Discovery

• Medicinal chemistry is a discipline combining biological, medical, and pharmaceutical sciences.
• It focuses on the discovery, design, identification, and preparation of biologically active compounds.
• It studies how these compounds work at the molecular level, including their structure-activity relationships and biotransformation.
• Medicinal chemistry is crucial in pharmaceutical industries, guiding the design and synthesis of new drugs for biological evaluation.
• A medicinal chemist needs expertise in organic chemistry and biological sciences to design and synthesize pharmaceutical agents with targeted effects on living systems.
• Drug discovery is a complex process involving numerous experts in various fields (chemistry, biochemistry, physiology, pharmacology, etc.).
• Medicinal chemistry plays a strategic role, bridging the gap between chemistry and biology.

Fields of Study in Medicinal Chemistry

• Invention, discovery, design, identification, and preparation of biologically active agents
• Studying the metabolism of drugs
• Interpretation of the mechanism of action of drugs
• Construction of structure-activity relationships
• Prediction of the biological activity of compounds from their physicochemical parameters

Course Objectives

• Predict biological responses from compound structures.
• Relate structural features to physicochemical properties.
• Forecast the biochemical mechanism of action of active compounds.
• Propose suitable analytical methodologies.
• Employ enzyme/receptor models to link chemical structures to biological activity.
• Predict biological responses from chemical alterations in biochemical pathways.

Drug

• A bioactive substance in a medicament that influences bodily functions, aiding in relief, cure, or disease prevention.
• Drug effects result from complex processes and interactions with biological systems.
• A drug's action involves three main phases: pharmaceutical, pharmacokinetic, and pharmacodynamic.

Drug Phases

• Pharmaceutical: Drug release from dosage form.
• Pharmacokinetic: Absorption, partitioning, biotransformation, and excretion (ADME).
• Pharmacodynamic: Interaction between the drug and its metabolites with specific binding sites.

Drug Sources

• Natural sources:
  • Mineral (9.1%): Inorganic substances like bicarbonate and ferrous salts.
  • Animal (8.7%): Hormones (e.g., insulin) and vitamins (e.g., from fish).
  • Plant (11.1%): Alkaloids, cardiac glycosides, antibiotics, and anticancer drugs.
• Synthetic (48.9%): Majority of today's drugs; organic, organometallic, and regioselective/stereoselective catalysts advancement in total synthesis of natural products (new analogues improved/simplified synthetic drugs).
• Semisynthetic (9.5%): Intermediate between natural and synthetic; fermentation products (antibiotics, amino acids, vitamins).
• Other (12.7%): Microbial drugs (antibiotics), sera, vaccines, and recombinant DNA technology for insulin production.

Drug Classification

• Pharmacological effect: Analgesics, antihypertensives, etc.
• Chemical structures: Quinolones, barbiturates, steroids, etc.
• Target system: Antihistamines, cholinergics, etc.
• Site of action (receptors): Anticholinesterase inhibitors.

Drug Discovery Methods

• Serendipity: Accidental discovery of a drug or a novel use of a known drug.
• Natural sources: Isolating active principles from plants, minerals, or animals.
• Random screening: Testing many compounds to find potentially active ones.
• Drug design: Rational approach, starting from the etiology of a disease to produce new drugs (e.g., ACE inhibitors).

Drug Discovery Process

• The process generally involves several steps using increasingly specific assays to narrow down the number of compounds to consider for developing as drugs.
• High-throughput screening is used for large-scale testing of compounds.
• Methods used include: strategic research, exploratory research, candidate drug selection, pre-clinical, and clinical development, FD/EMA review and approval, and post-approval.
• This leads to identifying and choosing candidate drugs to test and progress through clinical trials and FDA review.

Target Identification and Characterization

• Identifying the function of a therapeutic target (e.g., gene, protein).
• Validating the target: Determining if it has therapeutic benefit and acceptable safety.
• Using computational methods and databases, identifying potential hit candidates for development.

Drug Targets and Mechanism of Drug Action

• Drug action results from interacting with specific targets.
• Potential targets include enzymes, receptors, ion channels, and transporters.

Drug Receptor Interaction

• Drug molecules interact with specific sites on biological molecules (receptors).
• Drug targets: Receptors (proteins in cell membranes), enzymes, and DNA.
• Receptors play a regulatory role, and binding sites are defined as a receptor.
• Difference in interaction between enzymes and other receptors.
• Transduction events, initiating a cascade of intracellular events.

Signal Transduction

• A process where receptor activation leads to modifications in cell structure and function.
• Ligand-receptor interaction initiates a cascade.
• Receptor activation changes enzyme activity or channel gating.
• Cellular response can be magnified by increasing the level of intracellular messengers.

Drug Classification (Specific Drugs)

• Specific drugs have low concentrations and high tissue selectivity.
• Modifications in structure greatly impact a drug's activity (agonist to antagonist).

Drug Classification (Nonspecific Drugs)

• These drugs do not interact with specific receptors.
• Examples include general anesthetics.

Spare Receptors

• Some agonists produce maximum response without total receptor occupancy due to spare receptors.

Drug Affinity

• The role of chemical binding determines drug effects.
• Temperature affects in vitro drug testing.
• Drug-receptor interaction depends on chemical attractive forces (determining affinity).
• Critical bonds: Covalent, ionic, hydrogen, and hydrophobic.

Drug Receptor Theories

• Occupancy theory: Drug activity depends on the number of occupied receptors.
• Rate theory: Drug activity relates to the rate of drug-receptor combination.
• Induced fit theory: Conformational change in the receptor upon ligand binding.

Drug Discovery Process (Retrometabolism) Loop

• The process for creating new drugs and targeting based on structure-activity relationships and structure-mechanism relationships.
• Drug targets, prodrugs, and soft drugs (with less metabolic change during action).

Prodrug

• A compound inactive by itself that undergoes biotransformation in the body to become active
• Prodrugs are used to improve drug properties such as solubility, duration, site specificity, etc.

Prodrug Objectives

• Improving lipophilicity
• Enhancing water solubility
• Extending duration of action
• Improving acceptance by patients
• Suppressing undesirable properties of the original compound
• Increasing target site specificity in the body
• Increasing stability
• Examples include: esters of penicillin, steroids, etc.

Soft Drugs

• A new form of active drug designed with a metabolically soft spot.
• Metabolic deactivation is controlled by structural modifications, aiming at reducing or delaying metabolism.

Site-directed Drug Delivery

• Linking drugs to bile acids for targeting the liver.
• Creating drugs that only act within target locations, using enzymes or other mechanisms.

Site-Specific Drug Release

• Developing drugs that release active agents at a specific location or time.
• Using enzymes or other specific molecular mechanisms.