531 Unit 1 Lec 5-7

Eutomer

Eutomer

Active enantiomer

Distomer

Less potent enantiomer

Formula for Total number of stereoismoers of a chiral molecule

2 ^N

N= chiral centers

Methods to prepare enantiomerically pure forms of drug molecules

1)Use enentiomericallt pure starting materials

2)If the molecule has a carboxylic acid or basic amine, separate enantiomers at the END by making diastereomic salts

3)Use an enzyme to selectively modify one of the enantiomers of the racemate to facilitate separation OR prepare from an achiral starting material

4)Use a synthetic chiral catalyst to prepare one enantiomer at a key step in the synthesis from an achiral starting material

5)Separate enantiomers by chiral chromatography

Explain diastereomic salts

When you hace 2 enantiomers of an acid or base, adda single enantiomer of a base or acid to create a salt THEN separate those salts by their solubilities thus separating the enantiomers

Explain how to use an enzyme to

prepare enantiomerically pure forms of drug molecules

Attacks from only one end so it doesnt make both enantiomers

Esterases, redureductases, crases, and other enzymes can distinguish between enantiomers and create single enantiomers

Allows separation of racemic mixture by modify only one enantiomer, create single enantiomer from achiral starting material

Explain synthetic chiral catalysts

These catalysts act like enzymes in that they bind the starting molecule and modify it to produce mostly one enantiomer of a chiral product

→We made them

→D vs L , L (left), D (right)

→D vs L are specific for creating a certain enantiomer

Explain chiral chromatogrpahy

You have gunk, run it through a staw with hooks and the hook is specific for something, rinse out the gunk, rinse again to get it off the hook

• In this case, the hook is specific for an enantiomer

\n

Too expensive

What is synthetic biology

The use of recombinant DNA technology to create genetically modified organisms for the synthesis of novel products -For drug discovery usually for more efficient synthesis of bioactive molecules

What are chiral switch drugs

Development of a single enantiomer version of a racemic drug that has already been approved

No huge difference

Ex: Omeprazole→ Esomeprazole

What is torsional strain

lectrons repelling as the H atoms passing each other -Steric repulision if two spheres bigger than H

What is Baeyer’s Ring Strain

• Rings with small internal angles are highly strained: 3,4 membered rings

• For cyclohexane, the chair is the most stable

What is an exception to the rules of the most stable conformational isomers?

• Sometimes the most stable conformation is based on an intramolecular interaction that can override steric considerations

Ex: Acetylcoline, a highly flexible molecule, is surprisingly found in both solution and crystals in the gauch conformation

What is the bioactive conformation

The target/protein bound conformation.

How do rings improve binding affinity and specificity

• Increase affinity by reducing entropy loss upon binding

• Increase specificity because rigid molecule cannot access alternative bioactive conformations via bond rotations

Crosslinkers

Atoms that link two areas of a molecule to constrict its conformation. This pre-pays the entropic cost before the binding step

-This is part of rational design

What is drug residence time

-New evidence suggests that the main way to increase drug efficacy is to focus on maintaining the drug residence time (tau) (that is it bound to its target)

Induced fit

binding model in which a protein conformaitonal change is initiated by ligand binding because the ligand is inducing the change

Conformational selection

model which a  rare protein conformation binds the ligand directly

Lead optimization

Process of improving drug for use in humans and involves optimizing

ADME

ADME

→ Absorption: Modes of administration; if orally administered, transporting through epithelial lipid bilayers of GI tractto circulations

→Distribution: penetrations of tissues, passeing through cell membranes, crossing BBB

→Metabolism: Metabolic breakdown

→Excretion: consistent pattern of excretion

Lipinski’s rule of 5

1. Not more than 5 hydrogen bond donors

2)Total N + O atoms which are Hbond acceptors must be less than or equal to 10

3)Should have Less than 10 rotatable bonds

4)Should have Low molecular weight <500 daltons

5)Should have A 1 octanol water partition coefficient→ log P under 5

What bonds are not rotatable

amide bonds, ring bonds, double and triple bonds are not rotatble

Solute carrier proteins (SLCs) \n

import molecules into cells

→Organic Cation Transporter (OCT)

→Organic Anion Transport Protein (OATP)

ATP-Binding cassette proteins (ABCs)

export molecules out

Drug that are both extensively metabolized and are substrates for ABC/MDR/MRP efflux pumps have _____bioavailability

poor

BCS Group I

general good oral activiity

→High solubility

→High permeability

BCS Group II

Solubility is rate limiting step for absorption

→Low solubility

→High permeability

BCS Group III

permeability is rate limiting

→High solubility

→Low permeability

BCS Group IV

Usually low oral biavailablility . Often substrates for Pglycoprotein

→Low solubility

→Low permeability

Pka considerations for bioavailability

•CNS bioavailability requires neutral species for passive diffusion in addition to low MW •You want pka fraction as close ot neutral as possible •Acids absorbed in stomach, bases absorbed in small intestine