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Drug discovery > Lecture 8 > Flashcards

Lecture 8 Flashcards

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1
Q

What compound is considered a’hit’ during screening?

A

exhibits same activity within a statistically significant range

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2
Q

What value do hit rates of assay systems range between?

A

0.1-5%

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3
Q

What is the purpose of hit verification with confirmation screens and counter screens?

A

Establish a dose-response relationship in a secondary screen

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4
Q

What is meant by IC50?

A

Half-maximal inhibitory concentration

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5
Q

What are dose-response relationships expressed in?

A

IC50 in enzyme-, protein-, antibody-, or cell-based assays

EC50 in in vivo experiments

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6
Q

What is EC50?

A

half maximal effective concentration

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7
Q

What kind of information does the shape of dose-response curve provide?

A

info about hit’s mechanism of action (MOA)

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8
Q

What is the purpose of ‘counter screens’?

A

additional tests designed to identify false positives by ruling out compounds that act through non-specific or unrelated mechanisms.

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9
Q

What are the characteristics of counter screens and selectivity profile?

A
  1. profile action of hit on defined spectrum of biological target class
  2. include drug target of same protein/receptor family
  3. identify selectivity profile of hit
  4. additional info on MOA
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10
Q

What does high selectivity of a hit/lead indicate?

A
  1. low risk of off-target side effects
  2. better potency
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11
Q

An identified lead will enter the _________________.

A

lead optimization stage

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12
Q

Lead optimization is a process that

A
  1. refine chem structure to improve drug characteristics (stability + bioavailability)
  2. highly iterative
  3. often the bottleneck in drug discovery
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13
Q

What areas of research is lead optimization concerned with?

A
  1. med chem
  2. prelim pharmacokinetics and
    pharmacodynamics
  3. prelim toxicity
  4. pre-formulation studies
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14
Q

How is medicinal chemistry involved in lead optmization?

A

Analogues synthsized + screened

–>quant info that correlates changes in chem struct to biol and pharaco data –> SAR is established

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15
Q

In pharmacokinetics, why may a lead compound sometimes may fail to elicit the desired in vivo activity?

A
  1. not readily absorbed from site of administration
  2. rapidly metabolized or excreted
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16
Q

What are ADME/PK studies for?

A

absorption, distribution, metabolism, and excretion profile of drug

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17
Q

What are pharmacodynamics (PD) studies for?

A

Study
1. effects of drugs on the body
2. the drug’s mechanisms of action
(MOA)
3. relationship between drug conc and effect

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18
Q

Why toxicity studies?

A

evaluate the degree to which the drug can harm humans/animals

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19
Q

What are the 2 kinds of toxicities?

A
  1. acute toxicity
  2. chronic toxicity
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20
Q

What is acute toxicity study?

A

-Evaluate the harmful effects through a single or short-term exposure

-study lasts 1-2 weeks

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21
Q

What is chronic toxicity study?

A
  1. assess harmful effects over extended period thru repeated exposure
  2. lasts weeks to years
  3. may continue after human tests started to test for birth defects and cancer
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22
Q

What are some techniques/ways/methods/parameters to evaluate toxicity in In vitro studies?

A
  1. Cytochrome P450 inhibition
  2. MTT-like cytotoxicity assays
  3. Effects on cardiac HERG channels
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23
Q

What is to be evaluated during toxicity studies on animal models?

Study These Flashcards
A
  • Acute or chronic toxicity
  • Escalating dose studies
    —> Determine max tolerated dose
24
Q

What properties of the lead compounds have a major influence on selection of a proper formulation?

Study These Flashcards
A

physical, chemical, and mechanical properties

25
What is the purpose of formulation studies?
- determine how the drug is delivered into patients - other ingredients (excipients) added to the formulation
26
What is the ultimate goal of dosage form development?
develop a drug preparation that is stable and acceptable to the patients
27
What can dosage forms be divided into?
1. Liquid formulations --> Solutions, Syrups, Suspensions, Emulsions 2. Semisolid formulations --> Creams, Ointments, Gels 3. Solid formulations --> Tablets, Capsules, Suppositories, Pessaries, Transdermal patches
28
What are mot drug preparations formulated with?
- Active Pharmaceutical Ingredients (API) - Excipients that serve as lubricants, binders, preservatives, or antioxidants
29
What are some excipients?
lubricants, binders, preservatives, or antioxidants
30
What is an API?
the drug molecules that interact with the receptors or enzymes
31
What are some reasons to have excipients?
1. Control release of drug substance in the body 2. Enhance drug dissolution 3. Extend drug stability 4. Improve the assimilation process and bioavailability 5. Facilitate the manufacturing process 6. Mask the unpleasant taste of the API
32
What criteria shall new excipients to be included in a drug formulation have to meet?
1. Determined by FDA as “generally recognized as safe” (GRAS) 2. Approved by FDA as a food additive 3. Evidence showing that they have been tested in laboratory and clinical trials
33
Data from the PKPD study, toxicity evaluation, and formulation /delivery method studies will feed back into the medicinal chemistry effort to optimize the physicochemical properties of new leads in terms of:
minimal toxicity and maximal efficacy
34
What are some properties that must be evaluated and optimized in a lead before it becomes a drug?
1. potency, efficacy, selectivity 2. toxicity 3. ADME 4. stability 5. formulability (compatibility with excipients) 6. water solubility (for IV or IM injection) 7. pharmaceutical properties (taste, color, odor) 8. cost 9. patentability
35
What is the traditional linear processes of lead optimization? What approach has this process been replaced by?
traditional linear process: focuses on improving potency while excluding other considerations --> replaced by a more parallel approach, where drug-like properties taken into account simultaneously
36
What is the significance of Structure-Activity Relationships (SAR)-based lead optimization?
quantitative information that correlates changes in the chemical structure to biological and pharmacological data are generated to guide the optimization of the potency
37
What are structure-property relationship (SPR) studies?
structures of the leads are correlated to their property performance as opposed to potency in SAR studies
38
In SAR studies, structures of the leads are correlated to their _________________. However, in SPR studies, structures of the leads are correlated to their __________________.
-potency -property performance
39
Define 'drug-likeness'.
those compounds that have sufficiently acceptable ADME/Tox properties to survive through the completion of human Phase I clinical trial
40
How are in silico methods used to evaluate drug-like properties of a lead?
1. Lipinski’s Rule of Five 2. Apply a structural “filter” to eliminate compounds w/ reactive functional groups 3. drug databases as guide to rank the frequency of occurrence of specific molecular template and side chains. 4. Develop criteria to perform the drug/non-drug classification
41
Give an example of the in silico method of 'develop criteria to perform the drug/non-drug classification' in lead optimization.
identify the features required for the penetration of BBB or essential requirement for CNS active drugs, then apply a scoring scheme to the candidate molecules to distinguish drugs from non-drugs.
42
Why should in silico methods of lead optimization be applied with caution?
1. shld be considered guidelines rather than rules since none of the methods are much more than 80% successful 2. methods are also based on historic data --> unlikely that all future drugs will fall within their scope
43
Give some examples of drug-like strcutural properties
✓ H-bonding ✓ MW ✓ Reactivity ✓ Lipophilicity ✓ pKa
44
Give some examples of drug-like physicochemical properties
✓ Solubility ✓ Permeability ✓ Chemical stability
45
Give some examples of drug-like biocehmical properties
✓ Metabolism (phases I and II) ✓ Protein and tissue binding ✓ Transport (uptake, efflux)
46
Give some examples of drug-like pharmacokinetics (PK) and toxicity properties
✓ Clearance ✓ Half-life ✓ Bioavailability ✓ Drug-drug interaction ✓ LD50 or MTD
47
____________________ determine's the lead's fundamental properties and its behaviour when interacting with the physical environment (physicochemical) or proteins (biochemical properties).
compound structure
48
_______________ and __________ properties will be the determining factors for the pharmacokinetics and toxicity profile of the lead
biochemical and physicochemical
49
Compound structure determine's the lead's fundamental properties and its behaviour when interacting with the ____________________ or _______________.
physical environment (physicochemical) or proteins (biochemical properties)
50
biochemical and physicochemical properties will be the determining factors for the ___________ and __________ of the lead.
pharmacokinetics and toxicity
51
What is the purpose of emplying structure modification in lead optimization?
to improve the lead’s physicochemical and biochemical properties and to achieve the optimal PK and toxicity profiles
52
What are the 2 important physicochemical properties of a lead and why is it important to optimize them?
Solubility and permeability --> to achieve optimal oral bioavailability, reproducible discovery assay results, and BBB penetration (when necessary)
53
What are some strategies of improving solubility?
1. Salt form can be applied to compounds that contain ionizable groups 2. use amorphous state over crystalline state 3. alternative crystalline compounds, such as salts and co-crystals 4. pro drug approach 5. structural modification
54
Generally, the more stable the crystalline structure, the _______________ the material.
less soluble
55
Why is the prodrug approach to improve solubility of lead compounds not so common?
due to the cost (e.g., additional synthetic steps).
56
Give an example of a drug that was made more soluble with the prodrug approach
Fosphenytoin, the phosphate prodrug of phenytoin
57
What is one way of structural modification that leads to improvement in solubility of the lead compound?
Introducing ionizable centers such as a basic nitrogen --> ionizable amines --> sometimes advantageous to improve properties at the expense of potency

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