Exam 1

main components of a drug

active pharmaceutical ingredient (API) and excipient

active pharmaceutical ingredient (API)

specific compound that has the biological activity against protein target of interest

excipients

everything needed to make an effective drug that doesn’t cause biological activity against target of interest

small molecule drug classification

a drug with a simple structure and MW <1000g/mol

macromolecule drug classification

complex structure and MW >1000g/mol

how are small molecule drugs usually delivered

orally

how are macromolecule drugs delivered

parenterally (not orally)

types of therapeutics

peptide/protein based therapeutics and nucleic acid therapeutics

peptide/protein based therapeutics

drug that consists of amino acids

nucleic acid therapeutics (NAT)

drug that consists of nucleotides

medicinal chemistry field of study

focused on the discovery and optimization of small molecule APIs

pharmacology field of study

broad field of study on multiple aspects of drugs and medications

toxicology field of study

focused on the adverse effects associated with chemicals/drugs on the human body

pharmacodynamics field of study

focused specifically on what the drug does to the body

pharmacokinetics field of study

focused on what the body does to the drug after delivery

pharmaceutics field of study

focused on developing therapeutically useful API into a clinically useful drug

agonist definition

stimulates a biological response to produce a therapeutic effect

antagonist definition

drug that prevents a biological response to produce a therapeutic effect

are most drugs agonists or antagonists (what percent?)

antagonists (~90%)

FDA role in drug development

approves drugs for clinical trials and widespread human use

center for drug evaluation and research (CDER)

branch of the FDA that reviews applications and setsquality standards

types of FDA drug applications

investigational new drug and new drug applicants

investigations new drug (IND) application

submitted to the FDA before starting human clinical trials, includes preclinical data on efficacy and safety

new drug application (NDA)

submitted to the FDA to go to market and sell the developed drug, includes clinical trial data on efficacy and safety

first-in-class meaning

first drug on the market with a novel mechanism of action (new biology/pharmacology)

first-in-indication meaning

first drug available for a specific disease (new medical need)

list of the key drug features

affinity, selectivity, potency, efficacy, effectiveness

affinity definition

measure of how strongly a drug interacts with its target

selectivity definition

measure of how much more strongly the drug interacts with its intended target compared to other targets

what does higher selectivity mean for the drug

its a better drug with less off-target side effects

potency definition

quantitative measure of the drug affinity (expressed as concentration/dose)

what does higher potency mean for the drug

not as much drug needed for an effect, so lower doses are needed

efficacy definition

measure of the maximum response elicited by the drug

effectiveness definition

does the drug work in patients in the general population (clinical term)

target product profile (TPP)

defined set of planned goals for the development of a new drug, so each step has specific metrics to meet

the two types of target product profiles

essential and ideal

essential target product profile

minimum metrics the drug has to meet to continue in development

ideal target product profile

best case desirable parameters for the drug to meet

parameters included in target product profiles

indications, patient populations, therapeutic method, efficacy, safety, dosing/administration, approach, mechanism of action, biological activity

main questions to decide what disease to target with a new drug

• what population is affected by the disease?

• would it cure the disease or manage symptoms?

• do effective drugs already exist?

• why would a new drug be advantageous?

do most drugs cure diseases or manage symptoms

manage symptoms

main indications with most drug development

cancer, neurological diseases, dermatology, now obesity/diabetes

patent thicket strategy

one company files hundred of secondary patents after their initial drug to flood the market from biosimilars

examples of differences in secondary patents in patent thickets

new indications, new formulation, different administration/injection pen

example of a patent thicket

AbbVie did it with Humira to keep the top spot in drug sales for a long time

why was Keytrude very successful in the market

they achieved an ideal model because the drug works on all types of cancer (very large pt population)

bioequivalent definition

new generic drugs with the same API and mechanism of action as a brand name drug

when can bioequivalents be made

once the original brand name is off patent (20 years from filing for patent)

orphan drug

drug that treats an orphan disease

orphan disease

disease that affects a small population (<200,000 in the US)

incentive for companies to develop orphan drugs

• government grants for development

• tax breaks on clinical study costs

• extended market exclusivity after patent expires

target identification definition

identification of a biomolecule that plays a causative role in disease development or progression

most common drug targets

enzymes, GPCRs, ion channels, other receptors

what makes enzymes and GPCRs such good drug targets

they have natural small molecule binding sites and play major roles in disease states

primary target consideration in target identification

selectivity/specificity of the target protein (will alteration impact normal cells)

selectivity parameters in target identification

• target us only present in disease state

• reduction in target activity is enough

• controlled dose to maximize therapeutic effect without becoming toxic

examples of selective drug targets in antibacterials and antivirals

antibacterial: cell wall

antiviral: reverse transcriptase, proteases

on-target side effect

caused by biological activity of target protein when small molecule binds

consequences of on-target side effects in development

they can’t be designed out of a drug, so they kill development fast if they’re too detrimental

off-target side effect

caused by small molecule binding to something other than its desired target

consequences of off-target side effects in development

always occur since there’s never 100% selectivity, but they can sometimes be designed out of the drug to eliminate the side effect

target characteristics

macromolecules with hydrophobic binding sites containing some hydrophilic residues to cause interactions

role of intermolecular forces in drug targets

involved in binding interactions due to drug and target functional groups; impact affinity, which impact potency

what does high affinity mean for the drug

it will stay bound to the target longer, likely causing a greater effect

orthosteric site definition

enzyme binding site where the natural ligand interacts

orthosteric site as a drug target

more common target because we know more about these enzyme binding sites, and it may be similar on similar enzymes (like kinases)

consequence of orthosteric sites as drug targets

more potential for off-target side effects since they are similar across similar enzymes

allosteric site definition

potential enzyme binding site where the natural ligand doesn’t bind

allosteric site as a drug target

better selectivity since it’s more specific to certain proteins

consequence of allosteric sites as drug targets

harder to design drugs since we know less about the binding sites

what action to most drugs have on enzymes, why?

they inhibit enzymes, because it’s easier to inhibit than stimulate activity

classification of drugs used for enzyme targets

small molecules, since they’re intracellular

classification of drugs used for receptor targets

both small molecule and macromolecules since they can be targeted on cell surfaces or intracellularly

protein-protein interactions as drug targets

used mostly by cancer medications by using interaction sites between proteins as small molecule binding sites

consequence of protein-protein interactions as drug targets

binding sites aren’t as good since they aren’t used for natural ligands

DNA as a drug target

used to damage DNA in cancers cells

classification of drug used for DNA drug targets

macromolecules

consequence of DNA drug targets

non selective, since the drug just stops rapid growth and promotes early cell death (could impact healthy cells)

druggable proteins definition

proteins with tertiary or quaternary structures with binding sites that also lead to disease progression

how many proteins are druggable

15% total proteins

RNA as a drug target

RNA can form secondary and tertiary structures, which can act as small molecule binding sites, impacting cell signaling

classifications of drugs used for RNA drug targets

small molecules

example of drug that targets RNA

Risdiplam for spinal muscular atrophy

how Risdiplam works

binds to SMN2 gene in patients and stabilizes it, so it can produce more SMN protein

target validation definition

determination that a cellular target is causative of disease, and modulating the target will actually be therapeutic

best method for early target validation

patient data and clinical samples that demonstrate a clear link between the target and disease states

best overall target validation method

clinical results in human trials

general steps from hit to lead candidate in lead compound identification

1. compound screening

2. hits identification

3. lead identification

4. IND candidate (optimized lead)

5. candidate drug

hit compound definition

initial compound that has shown activity against a specific target in one experiment before

how are hit compounds identified

compound screening

lead compound definition

validated hit that has been tested 2+ tomes to show activity against a specific target

optimized lead compound/IND candidate definition

lead compound that has been modified to improve potency, efficacy, and PK properties

candidate drug definition

drug that has gone through clinical trials and is awaiting market approval

main types of lead compound screening

high-throughput screening and virtual screening

high-throughput screening definition

biochemical experiments in lab to find possible hits; often uses library of old experiments done for past hits

type of compounds lead compound screening is used for

synthetic

virtual screening definition

computational screening of compound libraries using software

types of virtual screening

ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS)

steps of ligand-based virtual screening (LBVS)

• use pharmacophore mapping to find important features of model small molecules

• screen models against compound libraries to find similarities

• identify potential leads from small molecules with similar structures and chemical makeups

steps of structure-based virtual screening (SBVS)

• screen for compounds that are predicted to interact with a specific target binding site

• run computer simulation to “dock” compounds on specific binding sites

• compounds scores based on their fit and potential ability to bind