Medicinal Chemistry concepts – Flashcards
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What does the subject of medicinal chemistry explain?
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The design and production of compounds that can be used for the prevention, treatment or cure of human and animal diseases
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What does medicinal chemistry study?
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Already existing drugs and their biological properties and structure-activity relationships (SAR)
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Who defines medicinal chemistry?
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IUPAC specified commission
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IUPAC specified commission defines medicinal chemistry as?
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The discovery, development, identification, and the interpretation of the mode of action of biologically active compounds at the molecular level
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What combination of sciences make up the study of medicinal chemistry?
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Organic Chemistry; pharmacology; pharmacognosy; computational chemistry; molecular modelling; biochemistry
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Organic Chemistry
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Is a sub-discipline within chemistry involving the scientific study of the structure, properties, composition, reactions, compounding, hydrocarbons, and their derivatives
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Physical organic chemistry
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Study of the interrelationships between structure and reactivity in organic molecules. The 2 main themes are structure and reactivity
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Combinatorial Chemistry
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The rapid synthesis of a large number of different but structurally related molecules, usually drugs. Usually robotic manufacturing is used to make a library of drugs
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Pharmacology
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Branch of medicine and biology concerned with study of drug action. Two major divisions are pharmacodynamics and pharmacokinetics
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Pharmacodynamics
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The study of actions of drugs on the body: what effects a drug has on the patient, including mechanisms of action beneficial or adverse effects or the drug and the drugs clinical applications.
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What is one of the most important aspects of pharmacodynamics?
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Molecular pharmacology
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Molecular pharmacology
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Study of pharmacology on a molecular level
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Pharmacokinetics
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Study of actions of the body on drugs. The absorption, distribution, storage, and elimination of a drug. Inverse of pharmacodynamics
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Pharmacognosy
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Study of medicines/drugs derived from natural sources
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Computational Chemistry
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Branch of chemistry that uses principles of computer science to assist in solving chemical problems including problems in medicinal chemistry. In silico is the use of computer systems to carry out research; mainly done just on the computer with things like simulations.
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Molecular Modelling
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Encompasses all theoretical methods and computational techniques used to model or mimic the behavior of molecules.
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What subject studies drugs?
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Medicinal chemistry
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What subject studies medication and the making of the medication using active pharmaceutical ingredients?
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Pharmaceutics and Bio-pharmaceutics
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What is broad def. of drug?
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All chemicals other than food that affect living process
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When is a drug a medicine?
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If drug helps the body
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When is drug a poison?
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If drug causes harmful effects to the body
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When is a drug both medicine and a poison?
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When the medication has too strong of side affects but at the same time helps the body in some capacity
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Drugs can also be defined as....
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Medicinal agents used for diagnosis, prevention, treatment of symptoms, and cure of diseases. Contraceptives would be outside of this definition unless pregnancy was considered a disease
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What is a side effect?
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Adverse drug responses which are unavoidable or appearing at therapeutic doses
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What is a toxic effect?
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Adverse drug effects appearing at extreme drug doses
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What are examples of some drug targets?
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-Lipids- cell membrane lipids -Proteins- Receptors, enzymes, transport proteins, structural proteins (tubulin) -Nucleic acids- DNA and RNA -Carbohydrates- cell surface carbohydrates, antigens and recognition molecules
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Why make smaller drug molecules instead of larger drug molecules?
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-Cheaper -Easier to understand -design easier to understand
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Drug targets are large molecules called?
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macromolecules
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Are drugs generally smaller or larger than their targets?
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smaller
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Drugs interact with their targets by binding to what?
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target binding sites
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Where are binding sites found?
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typically hydrophobic hollows or clefts on surface of macromolecules
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What is hydrophobic mean?
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water hating or nonpolar
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What type bonding do binding interactions typically involve?
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intermolecular bonds
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What type of bond are most intermolecular bonds?
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weak and reversible bonds
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What does a strong bond usually mean?
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Means it is usually lethal and irreversible which is not good
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What does a medium bond usually mean?
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Its not commonly used because it is most of the time irreversible
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What is the thought of the drug when it comes to its target?
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drug should fit the target and produce an effect but also be able to be revisable reaction
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Are most drugs in equilibrium between being bound and unbound to their targets?
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Yes, being bound and unbound to their target
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What is the involvement of functional groups on a drug and what are they called?
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-drugs are involved in binding interactions -they are called binding groups
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Specific regions within the binding site that are involved in binding interactions are called?
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binding regions
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Are drugs made to be selective or not selective when it comes to their target?
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selective
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Drug target selectivity between species
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-antibacterial, antifungal and antiviral agents -identify targets which are unique to the invading pathogen -identify targets which are shared but which are significantly diff. in structure
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Drug target selectivity within the body
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-selectivity between different enzymes, receptors, etc. -selectivity between receptor types and subtypes -selectivity between isozymes -organ and tissue selectivity
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When it comes to complex diseases such as depression where there are several diff. types of receptors that need to be affected throughout the body, would you use selective drug or less selective drug
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less selective drug; but most drugs are selective
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What tests must be done to find lead compounds?
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-in silico (computer simulations) -in vitro -in vivo -There is often a combination of two or three of these research methods
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What are in vitro research tested on?
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They are tested in a controlled environment outside a living organism. No animals/humans are used in these tests
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What are the target molecules in in vitro research?
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-they are isolated enzymes or receptors such as cells (closed cells); tissues (muscle tissue); organs; micro-organisms (for antibacterial agents)
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When is in vitro testing used?
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-its suitable for routine testing -used in high throughput screening
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What does in vitro testing measure?
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it measures the interaction of a drug with the target but not the ability of the drug to reach the target
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What is a positive of using in vitro testing?
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-results are easier to rationalize -less factors involved
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What are negatives of in vitro testing?
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-does not demonstrate physiological or clinical effect -does not identify possible side effects -does not identify effective prodrugs
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What is a lead compound?
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A chemical compound that has biochemical activity that is likely to be therapeutically useful; but still needs to be modified to fit its target
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What is in vivo research tested on?
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its tested on living organisms such as animals and humans
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What are the positive aspects of in vivo testing?
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-measures an observed physiological effect -measures a drugs ability to interact with its target and its ability to reach that target -can identify possible side effects -Are able to tell how potent the drug is -can usually find the therapeutic ratio/index from this study
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What are the negative aspects of in vivo testing?
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-rationalization may be difficult due to the number of factors involved
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What is drug potency?
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concentration of drug required to produce 50% of the maximum possible effect
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What is therapeutic ratio/index?
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It compared the dose level of drug required to produce a desired effect in 50% of the test sample ED50 versus the does level that is lethal to 50% of the sample LD50
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What type of test is the enzyme inhibiting test used in?
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in vitro testing
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What is a competitive inhibitor?
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The inhibitor has a similar shape to the usual substrate for the enzyme, and competes with it for the active site. However, once it is attached to the active site, nothing happens to it. It doesn't react - essentially, it just gets in the way.
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What is a non competitive inhibitor?
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A non-competitive inhibitor doesn't attach itself to the active site, but attaches somewhere else on the enzyme. By attaching somewhere else it affects the structure of the enzyme and so the way the enzyme works. Because there isn't any competition involved between the inhibitor and the substrate, increasing the substrate concentration won't help.
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In what way is the strength of inhibition measured?
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IC50
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What does IC50 mean?
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the concentration of inhibitor required to reduce enzyme activity by 50%
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Testing with receptors
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-not easy to isolate membrane bound receptors -carried out on whole cells, tissue cultures, or isolated organs. This is in vitro testing
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What does affinity mean?
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Strength with which compound bind to a receptor
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What does efficacy mean?
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measure of maximum biochemical effect resulting from binding of a compound to a receptor
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What does potency mean?
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concentration of an agonist required to produce 50% of the maximum possible effect
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What is a full agonist?
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this is a natural ligand which is found in the organ of the body -natural ligands are always full agonists
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What are some diff. types of agonists?
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full agonist and partial agonist
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Can a synthetic product be a full agonist? how?
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yes, if a synthetic product produces the same effect as a natural ligand it is considered a full agonist
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What is a agonist?
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sometimes called a full agonist; it produces maximum activation of the receptor and elicits a maximum response from the tissue. its assigned an intrinsic activity of 1
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What is a partial agonist?
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they produce weaker activation of the receptor than full agonists or the endogenous ligand (natural ligand). they produce only partial activation of the receptor and its downstream signaling events. The intrinsic activity is between 0 and 1
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What is an antagonist?
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it binds to receptor but produces no activation of that receptor and therefore blocks responses from the tissues. The intrinsic activity is 0
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What is a receptor conformation?
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these are 3D versions of the drug targets, can be any target in its 3D form
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What is competitive antagonism?
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This occurs when the agonist and the antagonist compete for same binding site on the receptor. would need more of either to outcompete the other
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What is pseudo-irreversibility?
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If the antagonist binds to the same site as the agonist but does so irreversibly. This doesn't usually matter how much agonist you apply because it is irreversible and if antagonist unbinds it will be a slow dissociation
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What is the allosteric effect?
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This occurs when the ligand binds to a different site on the receptor to either inhibit response or increase response. Effect is saturable meaning that inhibition reaches a limiting value when the allosteric site is fully occupied. Can cause conformational chance on the active site causing partial effect instead of full effect of the full agonist
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What is an Allosteric site?
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a site at which a small regulatory molecule interacts with an enzyme to inhibit or activate that specific enzyme; which is different from the active site where catalytic activity occurs. The binding of the allosteric effector is in general non covalent and reversible
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What is the therapeutic effect or curative effect?
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The dose at which 50% of the patients respond positively
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What is the toxic effect?
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The dose at which 50% of the patients show toxicity
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What is the lethal effect?
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The dose at which 50% of the patients die
