Medicinal Chemistry: Drug Discovery Process

• Medicinal chemistry focuses on discovering or designing therapeutic chemicals, turning them into useful medicines.
• This involves synthesizing and assessing new chemical entities for their biological activity.
• Medicinal chemistry is interdisciplinary, incorporating organic chemistry, biochemistry, pharmacology, and other biological specialties.

Drug Discovery Process

• Target identification identifies a specific biological target involved in a disease.
• Target validation confirms that modulating the identified target will have a therapeutic effect.
• Lead discovery involves finding a compound with activity against the chosen target.
• Lead optimization involves modifying a lead compound to boost its potency, selectivity, and pharmacokinetic properties.
• Preclinical studies assess a drug candidate's safety and efficacy in vitro and in vivo.
• Clinical trials evaluate a drug candidate's safety and efficacy in humans.
• Regulatory approval must be granted before a new drug can be marketed.

Drug-Target Interactions

• Drugs interact with biological targets like receptors, enzymes, ion channels, and nucleic acids.
• Chemical forces like hydrogen bonding, ionic interactions, van der Waals forces, and hydrophobic interactions govern drug-target interactions.
• Receptors are proteins that bind to specific molecules (ligands), triggering a cellular response.
• Enzymes are proteins catalyzing chemical reactions; drugs can inhibit or activate them.
• Ion channels are proteins that allow ions to pass across cell membranes; drugs can block or modulate them.
• Nucleic acids, such as DNA and RNA, are targets for some drugs, especially anticancer and antiviral agents.

Structure-Activity Relationship (SAR)

• SAR refers to the relationship between a drug's chemical structure and its biological activity.
• Modifying a drug's chemical structure can alter its potency, selectivity, and pharmacokinetic properties.
• SAR studies help medicinal chemists understand structural features needed for optimal activity.
• Quantitative structure-activity relationship (QSAR) is a mathematical model correlating a drug's chemical structure with its biological activity.

Pharmacokinetics

• Pharmacokinetics (PK) describes how the body affects a drug, including absorption, distribution, metabolism, and excretion (ADME).
• Absorption is the process by which a drug enters the bloodstream.
• Distribution is the process by which a drug spreads throughout the body.
• Metabolism is the process by which the body breaks down a drug.
• Excretion is the process by which the body eliminates a drug.
• Understanding a drug's PK properties is crucial for determining appropriate dose and dosing regimen.

Pharmacodynamics

• Pharmacodynamics (PD) describes how a drug affects the body, including its mechanism of action and therapeutic effects.
• Efficacy refers to the maximum effect a drug can produce.
• Potency is the amount of drug needed to produce a certain effect.
• Selectivity is a drug's ability to bind to its target and not to other targets.
• Therapeutic index measures a drug's safety.

Prodrugs

• A prodrug is an inactive or less active drug form that converts to its active form in the body.
• Prodrugs can improve a drug's absorption, distribution, metabolism, or excretion.
• Prodrugs can be utilized to target a drug to a specific tissue or cell type.

Drug Metabolism

• Drug metabolism, or biotransformation, is how the body chemically modifies drugs.
• Phase I metabolism involves oxidation, reduction, or hydrolysis reactions.
• Phase II metabolism involves conjugation reactions, such as glucuronidation or sulfation.
• Cytochrome P450 (CYP) enzymes are a family of enzymes playing a key role in drug metabolism.
• Drug interactions can occur when one drug inhibits or induces the metabolism of another.

Stereochemistry

• Stereochemistry studies the three-dimensional structure of molecules.
• Chiral molecules have a non-superimposable mirror image.
• Enantiomers are stereoisomers that are non-superimposable mirror images.
• Diastereomers are stereoisomers that are not mirror images.
• Stereoisomers can have different biological activities.

Combinatorial Chemistry

• Combinatorial chemistry synthesizes a huge number of compounds in a short time.
• This can generate libraries of compounds for drug screening.
• Solid-phase synthesis, used in combinatorial chemistry, performs chemical reactions on a solid support.

Peptidomimetics

• Peptidomimetics are small molecules mimicking the structure and function of peptides or proteins.
• They can be designed for improved stability, bioavailability, and target selectivity compared to peptides.
• Peptidomimetics are utilized as drugs or drug leads.

Natural Products

• Natural products are chemical compounds produced by living organisms.
• They have been a rich source of drugs and drug leads.
• Many important drugs, like penicillin, morphine, and Taxol, were originally isolated from natural sources.

Computer-Aided Drug Design (CADD)

• CADD uses computational methods to discover, design, and optimize drugs.
• Structure-based drug design uses the 3D structure of a target protein to design drugs.
• Ligand-based drug design uses the structures of known ligands to design new drugs.
• Molecular docking is a computational method predicting a drug's binding affinity to its target.
• Molecular dynamics simulations study the behavior of molecules over time.

ADMET

• ADMET stands for Absorption, Distribution, Metabolism, Excretion, and Toxicity.
• ADMET properties are important in drug discovery and development.
• Poor ADMET properties can cause drug failure.
• In silico ADMET models can predict the ADMET properties of drug candidates.

Drug Delivery Systems

• Drug delivery systems are formulations or devices used to deliver drugs to the body.
• These systems can improve a drug's bioavailability, efficacy, and safety.
• Examples include oral dosage forms, injections, transdermal patches, and inhaled medications.
• Nanoparticles are being explored as drug delivery systems.

Targeted Drug Delivery

• Targeted drug delivery specifically delivers drugs to the site of action.
• This can improve efficacy and reduce drug toxicity.
• Examples include antibody-drug conjugates and liposomes.

Emerging Trends

• Fragment-based drug discovery uses small chemical fragments to identify drug leads.
• DNA-encoded libraries are collections of compounds with linked DNA tags.
• PROTACs (proteolysis-targeting chimeras) are molecules inducing the degradation of target proteins.
• RNA therapeutics are drugs targeting RNA molecules.
• Artificial intelligence is being applied to accelerate drug discovery.