Drug Discovery Exam 2 – Flashcards
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| What is a hit? |
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| A compound that demonstrates activity in an assay that meets a threshold set by the investigator |
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| What are the four main types of patent claims? |
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| Composition of matter Method of use Method of manufacture Device |
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| Where is the application for a patent published? |
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| World Intellectual Property Organization of the UN |
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| When does a regular patent expire? |
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| 20 years after the filing date |
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| When is a regular patent application published by the WIPO? |
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| 6 months after the filing date |
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| What kind of patent does not require an examination? |
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| Provisional |
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| When does a provisional patent expire? |
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| 1 year after the filing date |
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| To whom are patents now awarded after the Leahy-Smith Act took effect? |
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| The first person to file rather than the first person to invent |
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| What are the 6 basic requirements for patentability? |
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| Usefulness Novelty Nonobviousness A written description Enablement Best Mode |
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| What are the main nonobvious characteristics? |
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| Improved absorption, metabolism, and efflux Activity against a different target |
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| What are the two components of enablement in a patent? |
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| How they were able to prepare and practice the invention, and teach others with "ordinary skill" how to do so |
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| What happens if a judge determins that a person with ordinary skill in the art would have contemplated a better mode of enablement than that described in the claim? |
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| The claim can be invalidated |
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| What do patent trolls do? |
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| Buy up patents in order to sue large companies to extort payment vs. large sums of legal fees |
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| What are the four main sources of hits? |
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| Screening Modification of standard Literature/patent mining Docking |
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| What are the five main sources for screening? |
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| Folklore/word of mouth Natural products/chemical defense Synergistic effects Microbial/soil samples Screening libraries |
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| What is the main limiting factor of screening? |
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| Cost/availability of reagents |
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| How are hits generated from screening? |
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| By running millions of assays through automation |
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| What does it mean for a hit to be a modification of the standard? |
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| Analogs/mimics natural substrates/modulators |
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| What are "me-too" drugs? |
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| Analogs that are essentially modifications of older drugs |
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| What are the main concerns about "me too" drugs? |
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| Cost of development Intellectual property |
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| What is required for docking? |
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| Known structural biology assets |
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| What are the three main methods of identifying the structural biology assets? |
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| X-ray crystallography Protein NMR Cryo-electron microscopy |
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| What is required to use biomolecule modeling? |
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| The protein sequence of the molecule |
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| How does biomolecule modeling allow you to create homology models? |
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| If you know the 3D structure of the target molecule, you can predict the structural results of small modifications |
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| If you have a target model, what can you use to find a hit? |
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| Programs such as DOCK and databases of chemicals |
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| What are the two main drawbacks of screening? |
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| Natural products often have poor PK Commercial libraries are heavily mined |
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| What is the main drawback of modification of standard? |
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| Typically synthetically complex |
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| What is the main drawback of literture/patent mining? |
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| Creating novel intellectual property |
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| What are the two main drawbacks of docking? |
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| Binding pockets are dynamic Lack of hard data |
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| What is the first step in confirming that a hit is real? |
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| Resynthesize and eliminate artifacts |
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| What is the strength of a covalent bond? |
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| 200kJ/mol |
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| What is the strength of an ionic bond? |
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| 30kJ/mol |
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| What is the strength of a hydrogen bond? |
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| 20kJ/mol |
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| What does SAR stand for? |
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| Structure activity relationship |
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| Why are drug interactions with covalent bonds not always desirable? |
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| Typically irreversible |
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| What is the most common type of interaction between drug candidates and targets? |
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| Hydrogen bonds |
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| What is the main requirement of a hydrogen bond acceptor? |
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| A lone pair of electrons on the heteroatom |
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| Is an amine a hydrogen bond donor or acceptor? |
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| Acceptor |
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| Is an alcohol group a hydrogen bond donor or acceptor? |
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| Both |
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| Is an ester a hydrogen bond donor or acceptor? |
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| Acceptor |
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| Are hydrogen halides hydrogen bond donors or acceptors? |
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| Both |
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| Are ethers hydrogen bond donors or acceptors? |
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| Acceptor |
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| Are ketones hydrogen bond donors or acceptors? |
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| Both |
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| Are aldehydes hydrogen bond donors or acceptors? |
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| Both |
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| Why are ketones and aldehydes considered both hydrogen bond donors and acceptors? |
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| They form geminal diols when placed in water, and they tautomerize into enols |
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| Why aren't carboxylic acids considered hydrogen bond donors? |
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| Because at physiological pH it is always an anion |
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| Are carboxylic acids considered hydrogen bond donors or acceptors? |
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| Acceptors |
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| What is the main hydrophobic interaction? |
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| Pi-stacking |
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| What does QSAR stand for? |
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| Quantitative structure activity relationships |
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| What is the benefit of making single changes? |
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| It allows you to directly relate those changes to activity |
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| To what do floppy molecules tend to bind? |
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| Albumin |
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| What does cyp tend to do to sulfur? |
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| Oxidize it |
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| What tends to happen to alcohols and amines? |
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| They are bioconjugated or oxidized |
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| What do benzene rings tend to attract? |
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| CYPs for oxidation |
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| What does the topliss tree assume? |
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| An unsubstituted benzene ring |
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| What are the two primary drivers for substitutents in a topiss tree? |
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| Sterics Electronics |
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| What is the logP? |
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| The log of the concentration that goes into water divided by the concentration that goes into 1-octanol |
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| What is the ideal logP |
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| 0-5 |
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| How do you use a table of pi values of aromatic substituents to predict changes to logP? |
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| Add the pi value of the substituent to the logP of the original compound |
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| What is the clogP? |
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| The calculated logP |
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| What three factors are typically considered in a Hansch analysis? |
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| Hydrophobicity Electronics Sterics |
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| What does QSAR stand for? |
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| Quantitative structure activity relationships |
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| What factors does QSAR try to incorporate? |
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| pKa Charge Dipole Moment Surface area Number of rotatable bonds Hydrogen bond donors and acceptors |
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| What does CADD stand for? |
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| Computer assisted drug design |
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| What do you use to determine if something binds to a protein or receptor if you don't have an assay? |
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| NMR shift |
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| What method of lead optimization does not require any knowledge about the target's binding site? |
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| Pharmacophore mapping |
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| How does pharmocophore mapping work? |
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| It looks for similarities among initial hits and proposes additional compounds to assay |
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| What are the two main drawbacks of CADD? |
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| Simultaneously changes multiple variables Most designed molecules are synthetically complex |
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| What are Lipinski's 5 rules? |
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| logP<5 Molecular weight<500g/mol Hydrogen bond donors<5 Hydrogen bond acceptors<10 |
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| How do you calculate logD? |
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| Log of the concentration of the drug in octanol divided by the sum of the concentration of the unionized drug in water plus the concentration of the ionized drug in water |
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| What is the pH of the buffer in which D is typically measured? |
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| 7.4 |
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| What are lipinski's three extended rules? |
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| logD<5 Rotatable bonds<10 Polar surface area<140 square angstroms |
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| What type of reaction is useful for binding fragments? |
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| Click chemistry |
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| What is the main premise of click chemistry? |
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| If two fragments are bound close enough together, they can be tethered while bound to their target |
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| What are the two main drawbacks of fragment-based discovery? |
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| Leap of faith that fragments are close by Floppy molecules (Bad PK) |
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| What are the four strong advantages of solid-phase chemistry? |
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| No multiple layers Can use excess reagents without affecting yield No cross couplings Can sequentially perform multiple steps |
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| Solid state media behave as what kind of group? |
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| Protecting group |
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| What kind of chemistry is used in automated peptide synthesis? |
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| Solid-phase chemistry |
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| What is the general idea of combinatorial chemistry? |
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| Making a lot of combinations of starting materials to generate a large number of products |
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| What is the primary drawback of solid-phase organic synthesis? |
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| Compounds are typically cleaved with trifluoroacetic acid |
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| What are the two drawbacks of using trifluoroacetic acid? |
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| Decomposition of the product Inefficient removal of TFA leads to a limited shelf life |
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| What is the suzuki reaction? |
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| [image] |
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| What is the buckwald reaction? |
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| [image] |
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| What is a good isostere for an alcohol group? |
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| Azide (N3) |
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| What is a common isostere for hydrogen? |
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| Fluorine |
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| Why is hydrogen replaced with fluorine? |
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| Carbon-fluorine bonds are not broken by CYPs Block oxidation of a methyl group |
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| What is a widely accepted carboxylate isostere? |
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| Tetrazole |
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| What can serve as a bioisostere for aromatic rings? |
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| Heterocycles |
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| What suffix generally indicates that a drug is a biologic? |
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| -ab |
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| What are the two main drawbacks of biologics? |
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| Only IV Very expensive |
