yr 2 options A Craven medicinal chem

what is a drug?

• a drug is a substance that has a physiological effect when introduced into the body of a living organism intended for use in medical diagnosis, cure, treatment or prevention of disease

pharmacokinetics vs pharmacodynamics

pharmacokinetics - what the body does to the drug

pharmacodynamics - what the drug does to the body

drug target interactions

• biological targets are big compared to small molecule drugs

• the key drug-target interactions usually happens in a local area of binding site

• protein/biological target interacts with the drug in the binding site through binding interactions that are usually non covalent

• there are several types of intermolecular bonding interactions which differ in their strengths - number and type present depends on the structure of the drug and the functional groups present

types of drug target interactions

1. electrostatic/ionic bonds

2. van der waals interactions

3. pi-pi interactions

4. hydrophobic interactions (the only one thats entropic not enthalpic)

5. hydrogen bonds

electrostatic/ionic drug target interactions

• not very common but when present are usually the strongest interactions - almost always stronger than hydrogen bonds

• eg. between NH₃⁺ and COO^- an ionic interaction (salt bridge) can be formed

• An enthalpic effect

• binding energy: 5-300 KJmol^-1

van der waals drug target interactions

• simple induced dipoles and their attractive forces

• exist in all drug-protein interactions and can’t really be altered so mostly uninteresting

• An enthalpic effect

• rough binding energies: 0-10 KJmol^-1

pi-pi drug target interactions

• interactions between two aromatic rings (have clouds of electron density above and below the ring)

• usually leads to regions of electron density building up in those areas but if you place and EWG or use electron deficient heteroaromatics, you can flip this and create a positive charged area that can stack onto another aromatic ring

• pi-pi stacking

• An enthalpic effect

• binding energy: 1-5 KJmol^-1

hydrophobic drug target interactions

• an entropic effect

• the water molecules surrounding the drug have to be stripped away before other interactions can take place

• this takes energy and if energy is required to desolvate both the drug and the binding site is greater than the stabilisation energy gained from the binding interactions then the drug may be ineffective

• however inclusion of hydrophobic regions in drugs can aid binding as the water that would have been near this hydrophobic region can now interact more favourably with other water molecules

• water returned to bulk (from hydrophobic region on drug- highly ordered water region) when drug and protein bind create lots of degrees of freedom in water therefore a large entropic gain

• majority of binding comes from hydrophobic effects but this is generally non-specific

hydrogen bond drug target interactions

• probably the most important interaction when it comes to specificity (binding to one target over another)

• strength can vary from 16-60 KJ mol^-1 (usually 12-20)

HBAs

• anything with a partial negative charge

• teh more negative the charge the stronger the H-bond

• carboxylate > phosphate > carbonyls > alcohols/amines/ethers? > R₂S/R-Cl

HBDs

• generally an electron deficient hydrogen linked to O or N

• the more electron deficient the stronger the bond formed

• R-NH₃⁺ > R-OH > R-NH₂ or Ph-NH₂ (not good HBAs)

drug target interactons summarised in an energy diagram

quantifying interactions (IC50)

• IC50 = inhibitory concentration - 50% effect

• eg. the conc of a drug needs to kill 50% bacteria / have 50% effect - measure in M

• look at photo for keq and Ki

• ∆G = -RT ln(eq) therefore ∆G = RTlnKi

pKa estimates - acids

acid- lower pka - stronger acid

• ethanoic acid - 5

• phenol - 10

• tetrazol - 4.5

• sulfonomide - 4

pka estimates - bases

base - higher pka - stronger base

• NH3 - 9

• MeNH2 , Me2NH - 11

• Me3N - 10

• imidazole - 8

• pyridine - 5

• alinine - 5

• availabiliity of lone pair or stability of +ve charge dictates basicity

pka estimates - neutral

• ketones

• carboxomides

• ethers

amines - trends in pKa

electron donating r groups tend to increase basicity

• makes lone pair more available

• stabilises resultant positive charge

electron withdrawing r tend to reduce basicity

• makes lone pair less available

• destabilises resultant positive charge

number of substituents

• in aqueous solution need to consider teh solvation by water as weel - this stabilises the positive charge we make which increases basicity

• solvation by H20 increases with more N-H bonds (more capability to h bond with H2O) - this works against EDGs (ankyl groups) so primary adn secondary are more basic that tertiary amines and NH3

acids - trends in pKa

electron donating r groups tend to reduce acidity

• destabilise -ve charge

electron withdrawing r groups tend to increase acidity

• stabilise -ve charge

determining extent of ionisation of compound

for acids

• fraction unionised = 1/1+10^(pH-pKa)

• pH = pKa : 50% unionised

• pH = pKa -1 : 90% unionised

• pH = pKa -2 : essentially completely unionised

for bases

• fraction unionised = 1/1+10^(pKa-pH)

• pH = pKa : 50% ionisedlipo

• pH = pKa -1 : 90% ionised

• pH = pKa -2 : essentially completely ionised

lipophilicity

• a measure of how ‘greasy’ a compound is ie. how much it likes lipids (fats) and equivalent to hydrophobicity (how much water it hates)

lipophilic functionality includes:

• aliphatics

• aromatics

• halogens (not all solvated by water despite lone pair)

polarity

• a measure of how hydrophilic a compound is

polar functional groups include:

• alcohols

• amines

• amides

ligand efficiency

• a useful value for describing the efficiency of a drug’s binding to a target- some of the binding of a drug to a target is driven by hydrophobic interactions

• hydrophobic interactions generally increase with the size of the molecule so we would expect larger molecules to bind better given all other binding interactions being equal

• these interactions are key to specificity though so LE looks to remove hydrophobic interactions from the equation

• same ∆G for and increasing N therefore less good binder and decreased LE

• use heavy atom count as all atoms bar hydrogen typically contribute to hydrophobic effects

• It is now widely used in drug discovery as it can identify high quality hits with a small binding energy which might get lost otherwise

• through the drug discovery process LE will generally stay the same

equation for ligand efficiency

LE = -∆G_binding / N

• LE = 1.4 (-logKi)/N

• LE = 1.4pKi/N

• convert from J → cal Kcal = kj/4/184

• n = number of heavy atoms ie. not hydrogen

lipophilic ligand efficiency (LipE)

instead of linking the binding to heavy atoms count this links it to logP as this links more directly to hydrophobic interactions

• lipE = pKi -LogP

• (pKi = pIC50)

• high quality compounds that aren’t binding through hydrophobic effects have a high LipE eg above 6

quantifying lipophilicity and polarity

logP/logD and pKa for acids

• log D is ALWAYS smaller than logP - not just in acidic conditions

• when unionised logP=logD

• dip starts just before pKa = pH

logP/logD and pKa

what does this graph tell you about this compound

difference between logP and logD

• both a measure of lipophilicity / hydrophobicity

• LogP treats the molecule as neutral

• LogD looks at the ionisation of the molecule as well - dependant on the pH its measured at as this alters the ionisation of the drug

Calculating logP

• often calculated using ‘fragmental calculators’

• assume logP is an additive property ie. addition of a group changes logP by the same amount each time - falls down primarily when functionality changes

• calculated logP = ClogP

• can estimate logP based on fragments

• H = 0

• lipophilic substituents: pr > Me > Et > Cl > CF3 > Ph > F (positive values)

• polar substituents: SO₂Me > SO₂NH₂ > CONH₂ > CN

pharmacodynamics

• study of the pharmacological response to a drug

• desired effects due to activity at the biological target ‘potency’

• undesired effects due to activity at other targets ‘selectivity’

• basically what the drug does to the body

pharmacokinetics

• study of the movement of a drug through the body

• absorption, distribution, metabolism, excretion (ADME)

• gives an indication of the likely exposure of the drug in the body

• basically what the body does to the drug

where does the drug go?

gut —(absorption)—> blood —(when drug can do its work)—> liver/kidneys —(elimination)—> excrete

• brain - unique membrane between blood and brain called blood brain barrier - protects brain from things in blood

• oral delivery - most common method

• heart - very specific tissues/ion channels to worry about

• stomach + intestine - GI tract, this is where we absorb the drug into blood

• liver + kidneys - key organs in the excretion of drug

oral drug profiles

• to monitor the absorption and elimination of a drug medicinal chemists will construct drug profiles of their drug in vivo

importance of half-life

elimination half life is the time taken for drug plasma concentration to reduce by 50%

• for ideal administration of oral drugs we want 24h doses

• the shorter the half life the greater peak to trough ratio- need higher dose to maintain Cmin > efficacy

• unless the drug is very safe once-a-day dosing requires a long half life eg. longer than 12 hours

• half life is driven by two independent factors - volume of distribution and clearance

• dosing must be carefully controlled to ensure that the plasma concentration remains in the therapeutic window

• first graph is the single dose profile

• second graph is the steady state profile - shows max safe and minimus efficacy concentrations

what are the 6 components of ADMET - key pharmacokinetic ideas

1. absorption

2. distribution

3. metabolism

4. excretion

5. elimination*

6. toxicity

absorption

• process by which our body absorbs the drug

• for oral drugs = GI tract - 4 main types

• paracellular (molecule squeezing between cells in the gut wall) -rare

• transcellular - passive diffusion (by far the most common)

• transcellular - active transport (cell actively pulls drug through gut wall)

• transcellular - efflex pumps - essentially the opposite of active transport - cells push drugs back into GI tract

factors to consider when looking at the absorption of a drug

logP

• too polar - less able to desolvate and enter highly non-polar cell membranes

• too lipophillic - may permeate cell membrane but fail to exit into aqueous media on the other side

ionisation

• generally ionised compounds will not cross the cell membrane - do not line lipids

• can use prodrugs to mask ionisable functionality until it reaches the target eg. masking carboxylic acids (carboxylates at body pH) as methyl esters which are non-ionisable so absorbed well but inactive - converts back to active form in vivo after absorption

• altering basicity d a compound can lead to significant changes in permeability/absorption

• altering pKa from 99% ionised to 90% ionised for example ensures enough drug is neutral for absorption to occur

• follow lipinskis rules

Lipinski’s “rules” and the birth of cheminformatics

a drug has poor absorption if it obeys more than one of the following rules

• ClogP < 5 _{(don’t want compound too greasy)}

• molecular weight < 500 _{(don’t want compound too greasy)}

• HBD <5 _{(not too polar or it wont want to leave water - too many H bonds therefore not absorbed)}

• HBA <10

• this sparked a revolution in cheminformatics (computional) in drug discovery

distribution

• transfer of a drug from the blood to the tissues eg. where site of action exists

metabolism

• modification of the drug by the body to help it be excreted

excretion

• transfer of drug out of the body eg. urine, faeces

elimination

• either the same as excretion (what phil uses) or combination of metabolism and excretion

toxicity

• assessing the side effects - fundamentally caused by drug binding to other targets

• unique to a drug class - some common liabilities eg. hERG ion channel - spans most small drugs

• blocking hERG channels leads to prolongation of QT interval leading to fatal cardiac arrhythmias

• common motif (toxicoplane) that causes hERG liability show in photo

Volume of Distribution (Vd)

volume required to hold all drug added to the system (body) at the same concentration to that measured in the circulating compartment (blood) - a theoretical parameter

• a measure of how well the drug distributes out of the blood into the tissues- units L or l/kg - small values suggest a drug is closely confined to plasma and doesn’t distribute well to tissues

• x mg of drug in one dose - if all absorbed and all staying in blood then plasma concentration = x/volume of blood in the body (3.5 L)

• Vd = dose / drug concentration in plasma

• small values = minimal distribution

• large values = large distribution

• neutral and acidic compounds tend to have limited distribution into tissues and have low volume of distribution (0.2-2 L/kg)

• basic compounds display a higher volume of around 0.5-30 L/kg

• as a general rule, Vd tends to increase with increasing lipophilicity

clearance

• part of the elimination pathways

• the rate at which a compound is removed from systemic circulation (via any method)

• usually described in mL/min/kg

• primarily through kidneys or liver or both

• CL = Q x Er

• Q = blood flow - for liver = 20 mL/min/kg

• Er = extraction ratio = increased Er = increased clearance

• [X]a → liver→[X]b (blood with drug) or → clean blood

half life relationship to Vd and CL

• C = C_max e ^-Ket

• C_^t = C_⁰ e^{-kel t}

• K_el = CL / Vd

• t_1/2 = 0.693/K_el = (Vd x 0.693)/CL

• an increased Vd leads to an increase in half life and an increase in CL leads to a decrease in half life

• Vd more widely distributed means less drug moving through the liver

metabolism phase 1

initial alteration of functionality to something more polar

• OXIDATION

• eg. hydroxylation- usually happens on aromatics or adjacent to heteroatoms

• N,S-oxidation → amine → N-oxide (R₂N-O^-) or R₂S → R₂SO₂

• N, O, S - dealkylation

• REDUCTION

• carbonyls to alcohols

• -NO₂ → -NH₂

• HYDROLYSIS

• of esters or amides

metabolism phase 2

appendage of natural functionality to produce highly polar substrates

• GLUCRONIDATION

• add a sugar (glucose) to an alcohol

• SULFONATION

• adding sulfate (SO₂OH) to alcohol

• SILDENAFIL’S route of metabolism (on separate flashcard)

SILDENAFIL’S route of metabolism

reducing metabolism

• primarily done through ‘blocking’ the site - generally a C-H we’re trying to get rid of

• eg. adding Fs is a classic approach as its nor much bigger than H but the C-F bond in strong

• or altering an ether to an sulfoxide ie. R₂O → SR₂O₂

• need to be aware of admet changes though

• not always that simple though, the metabolic enzymes involved tend to interact more strongly with more lipophilic substrates

• often a correlation between logD and elimination and for compounds with logD >3 then reducing logD is the best tactic

• for compounds with logD >3 then blocking the metabolic site often just moves the site of metabolism to somewhere else.

bioavailability (F)

%F = % of administered dose reaching systemic circulation (bloodstream)

a key pharmacokinetic parameter - determines the relationship between the administered dose and the concentration of drug in the body

• AUC (area under curve) is proportional to %F

• increased absorption - increased F

• increased distribution - increased F

• decreased metabolism - increased F

• decreased elimination - increased F

natural products

• natural products have evolved to interact with biological systems - why would an organism waste energy making something that couldn’t interact with biological systems

• 63% of small drugs are derived/inspired by natural products

• eg. penicillin, lovastatin

fast follower approach

sometimes a new drug that comes along is described as first-in-class or blockbuster - drugs that do something new or different either treating a previously untreatable disease or targeting a new biological target within the same disease area

• more often new small molecule drugs are described as fast-follower or ‘me too’ drugs - where a company takes an already developed drug compound and adapts it to make it better whilst avoiding patent infringements

high-throughput screening (HTS)

• the vast majority of compounds synthesised don’t reach the market and are instead stored un libraries and are routinely tested against new biological targets

advantages

• cheap if you have the equipment bc you already have compounds

• get lots of info very quickly

• head start on synthesis

disadvantages

• using ‘bad’ compounds eg. may be effective but safety concerns

• not exploring chemical space - focused on areas already explored

• hit or miss - what happens if none hit?

phenotypic screening vs target-based drug discovery (TBDD)

drug discovery was historically achieved by testing patients/animals with drugs and seeing what happened - this is phenotypic screening as the phenotype is the treatment of the disease - care about how it works not why (only learn why they work as chemical/biological techniques advance)

TBDD - more recent - identify a biological target that we think should treat a disease then test molecules against that target - but even if you find a compound capable of initiating a target there’s no guarantee it can do so in vivo and even if it can there may be many other complication in the biological system

so phenotypic screening has returned to the forefront

advantages of phenotypic screening

• studies have shown that phenotypic screening is more effective at getting first-in-class

• more confidence in in vivo activity - pharmakokinetics

disadvantages of phenotypic screening

• what is the mechanism of action? net target which is lots of effort to find

• TBDD is shown to give better best-in-class drugs

virtual screening

what if you don’t have compounds or are unable to store them?

solution is to run screening in silico - virtually

• need crystal structure of protein of interest

• then ‘dock’ compounds with the protein

• gives starting point

serendipity

• lead compounds are often found as a result of serendipity ie. chance

• but their discovery required someone with an inquisitive nature to recognise the significance of chance discoveries and take advantage of these events

• the discovery of cisplatin and peniciliin are the two most famous

• eg. chlormethine and cyclophosphamide - survivors of mustard gas attacks were more susceptible to to infections - shown white blood cell counts were down - treatment for leukemia that causes excess white blood cells

• glyceryl trinitrate - explosive industry - workers often suffered headaches - resulted from dilution of blood vessels in the brain - oral tablet used to treat angina

• disulfiram - rubber industry - acquired a distaste for alcohol - antioxidant prevented oxidation of alcohol - build up of acetaldehyle - very unpleasant - used as a treatment of alcohol addiction