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29 Cards in this Set
- Front
- Back
- 3rd side (hint)
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What is the basis of rational drug design? |
All molecular machinery operates on a 3D level |
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Explain the Lock and Key theory |
It is the specific action of an enzyme with a single substrate. Only the correctly sized key (substrate) fits into the key hole (active site) of the lock (enzyme) |
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Explain the induced fit theory? |
Enzyme is flexible and the active site will assume the shape of the substrate. The enzyme can become distorted and lose its activity- thats why certain compounds can bind to the enzyme but do not react because the enzyme has been distorted too much. |
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What are the steps of the rational design process? |
1) design of compounds 2)molecules are synthesized and tested 3)refinement and optimization of the lead compounds |
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What are the 2 rational drug design approaches? |
1)receptor based drug design 2)pharmacophore based drug design |
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Explain the receptor based drug design approach |
Finds the 3D structure of the target using X-Ray crystallography or NMR |
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How is receptor based drug design done? |
Active site identification : 1)analyse protein to find binding pocket 2)derive interaction sites in the binding pocket 3)prepare necessary data for ligand design |
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What molecular properties of the active site should be defined? |
Hydrophobic atom - C in hydrocarbon chains/aromatic groups H-bond donor - O and N bonded to H H-bond acceptor - O and sp or sp2 hybridized N with lone electron pair(s) Polar atom - O And N accept S/P/H/metal/C bonded to heteroatoms |
HHH-P |
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Explain the pharmacophore based drug design approach |
1)target and active site identification 2)QSAR 3)pharmacophore based screening 4)computational and experimental validation |
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Explain target and active site identification |
Identify natural target enzyme Generate its 3D structure using NMR/XRC Identify active binding pocket of target enzyme |
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Explain QSAR step |
Identify molecules that fit into the active site Establish structural relationship between molecule and target Identify molecular recognition sites and correlate structural and chemical descriptors of the compounds based on the SAR |
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Explain pharmacophore based screening step |
Screen for other compounds which have similar structural properties to that generated molecule from QSAR |
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Explain computational and experimental validation |
After computational analysis the best chemically/structurally favourable potential leads are validated by in vivo/in vitro studies |
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What are the physicochemical properties? |
Molar refractivity Electronic effects Steric effects Hydrophobicity |
MESH |
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Explain molar refractivity |
Measure of the volume occupied by an atom or group of atoms |
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What is the verloop steric parameter? |
Measure of the steric factor. Can be computed to calculate the steric substituent values |
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Explain electronic effects |
Has an effect on ionization or polarity-how easily a drug can pass through cell membranes or how strongly it can bind to a receptor |
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What is the hammett substitution constant? |
Measure of electron withdrawing or electron donating ability of a substituent. Measured by measuring the dissociation of a series of substituted benzoic acids compared to dissociation of benzoic acid itself |
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Explain steric effects |
The effect of the bulk,size, shape of the drug on its approach and interaction with an enzyme or receptor. |
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What is taft's steric factor? |
Measure of intramolecular steric effects. Obtained by comparing the rate of hydrolysis of substituted aliphatic esters against a standard ester. |
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Explain hydrophobicity |
How easily the drug crosses cell membranes and receptor interactions. Tested in octanol/water mixture |
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What is the hansch equation? |
Relates the biological activity of drugs to the most common physicochemical properties |
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Explain the use of the table of substituent constants for various physicochemical properties? |
Knowledge of these constants allows us to identify substituents which may be potential bioisosteres. |
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What is ADME? |
Part of pharmacokinetics A-absorption D-distribution M-metabolism E-excretion |
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Absorption? |
The process of a substance entering the blood circulation |
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Distribution? |
The dispersion or dissemination of substances throughout the fluids and tissues of the body |
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Metabolism? |
The irreversible transformation of parent compounds into daughter metabolites |
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Excretion? |
The elimination of the substances from the body |
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What is denovo design? |
Generating virtual lead compounds entirely through computer simulation |
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