Linking Chemistry and Drug Action

edX D001x: Medicinal Chemistry

Erland Stevens Davidson College

AP and IB content references

•AP Chemistry: Course and Exam Description Revised Edition Effective Fall 2014

• IB Diploma Programme: Chemistry guide First assessment 2016 (©2014)

AP page references IB page references

D001X – an online chem course Title Medicinal Chemistry: The Molecular

Basis of Drug Discovery

Location www.edx.org

Cost free

Length 8 weeks (~1 hr video/wk)

Start date Mon., Oct. 5, 2015 (also Mar. 2016)

Outine: Chemistry → drugs

1. Hydrogen bonding → oral drug absorption

2. Equilibrium & free energy changes → drug-protein binding

3. First-order kinetics → drug half-life

4. Acidity & basicity → volume of distribution

#1 – Hydrogen bonds

•H-bond donor (HBD) – N-H or O-H (or F-H)

•H-bond acceptor (HBA) – N or O (or F) lone pair

•Strong intermolecular force (2-3 kcal/mol)

Y H Y

Y = N , O , o r F

H - b o n dd o n o r

H - b o n da c c e p t o r

Y H Y

h y d r o g e n b o n d

EK 2.B.2, p 25 EK 5.D.1, p 61 Topic 4.4, p 48

Drugs form H-bonds with water

Drugs with HBAs and HBDs form H-bonds with water. These H-bonds hold the surrounding solvent shell to the drug.

O

OH

O

O

HOH

H

OH

HOH

HOH

HOH

HO

H

H

OH

H

OH

H

OH

H

OH

HOH

HO

H

Oral drugs must cross cell membranes

To cross a membrane, the drug must shed its polar solvent shell (desolvate).

drug in thesmall intestine

(polar medium)

drug in theblood stream

(polar medium)

drug in thecell membrane

(non-polar medium)

D

D

D

D

D

D

D

D

DD

D

D

D

Lipinski’s rules

•Simple rules to predict whether a molecule will be orally available (Chris Lipinski – Pfizer)

•# allowed HBD (OH & NH) <= 5

•# allowed HBA (O & N) <= 10

Lipinski, C. Adv. Drug Deliv. Rev. 2001, 46, 3-26.

#2 – Equilibrium & free energy

The difference in free energy between a reaction’s products and reactants allows quantification of the reaction’s equilibrium.

EK 6.D.1, p 80 Topic 4.4, p 48

How (most) drugs work

•Drugs bind reversibly to a specific protein, or target, in the body.

•Bound drug interferes with the natural action of the protein.

•Changes in protein action lead to changes in the disease state.

Drug-protein binding

KD is the dissociation equilibrium constant and is used to measure how well a drug binds its target. Lower values of KD indicate a more potent drug.

Binding of “hits”

•hits – weakly active binders of a target protein

• typical KD = 1×10-6 M (1 µM)

•binding energy (ΔGbind) = −8.2 kcal/mol

Sample calculation

Binding of drugs

•drugs – highly active binders of a target protein

•KD = 1×10-8 M (~ 10 nM)

•ΔGbind = −10.9 kcal/mol

Intermediate between hits and a drug → leads. Leads are optimized into drug.

Intermolecular forces

•Hydrogen bonds

•Dipole forces

•London dispersion forces

•Hydrophobic effect (entropic)

Lead optimization

#3 – First-order kinetics

EK 4.A.2, p 47 Option C.7, p 152

Drugs have half-lives

Cp (

ng

/mL)

time (h)

Cpo

0.50 Cpo

0.25 Cpo

t1/2

2 t1/2

Cp-time data for drugs

•Cp = plasma concentration (often ng/mL)

• time is normally in hours (h), sometimes days (d)

• t1/2 is set by kel, the elimination rate constant

•kel is determined by liver metabolism and kidney filtration → a patient’s kidney and liver health affect kel and t1/2

Half-life of theophylline

condition t1/2 (h)

healthy adult 8.7

cirrhosis 32.0

pregnant (3rd trimester) 13.0

toddler (1-4 yo) 3.4

theophylline

Drugs have half-lives

#4 – Acidity and basicity

•Parts of a molecule can be protonated or deprotonated depending on their activity (pKa) and the pH of the environment.

•Protonation and deprotonation change the charge state of the molecule.

EK 6.C.2, p 77 18.2, p 92

Apparent volume of distribution

•Apparent volume of distribution (Vd) – a hypothetical volume of plasma required to contain a drug in the body.

•Plasma is the non-cellular portion of blood.

•Vd affects kel and therefore t1/2.

Determining Vd C

p (

ng

/mL)

time (h)

Cpo

•Cpo – estimated from

experimental data

•Do – initial dose (known)

•Vd – determined by calculation

Conceptualizing Vd

plasma volume (2.7 L for

70-kg patient)

drug in plasma only (Vd = 2.7 L)

mostly plasma some periphery

(Vd > 2.7 L)

some plasma mostly periphery

(Vd >> 2.7 L)

Drug structure & Vd

acidic drugs have lower

Vd

values

basic drugs have

higher Vd

values

general trends

Acidic drugs & Vd

Basic drugs & Vd

Vd and t1/2

volume of distribution

clearance

Drugs with a high Vd have a longer t1/2.

Example of Vd manipulation

Di, L. J. Med. Chem. 2015, 58, 5691-5698.

NH

O

O

O

ONO2

nifedipine(Procardia)

antihypertensive

Vd = 55 LCL = 511 mL/min

t1/2 = 1.9 h

NH

O

O

O

OC l

a m l o d i p i n e( N o r v a s c )

a n t i h y p e r t e n s i v e

V d = 1 , 1 9 0 LC L = 4 9 0 m L / m i n

t 1 / 2 = 3 4 h

ON H 2

Next MOOC launch

• MOOC = massive open online course • Medicinal chemistry on www.edx.org • Launch – October 5, 2015 • Completely free • Potential next run – March 2016

Prerequisites

•Algebra 2: exponents and logarithms

•HS biology: cell parts and function

•HS gen chem: equilibrium, free energy, acidity

•Some organic chem: line-angle notation & FGs

C

CCC

CCH

H

H

O

H

CO

O

CCO

H

H

HH

OH

O

O

O

Overview of MOOC topics

Week 1 – drug approval process Week 2 – proteins as drug targets Weeks 3 & 4 – pharmacokinetics & metabolism Week 5 – drug binding and diversity Weeks 6 & 7 – lead discovery & optimization Week 8 – selected drug classes

Performance of past HS students

• Previous run – October 2014

• Students of age 14 to 18 – 699

• HS students viewing all of course – 31

• HS students passing course – 7

To complete a brief questionnaire

about this webinar, and to generate

your certificate of attendance, visit:

http://bit.ly/aactpd

To download resources: http://bit.ly/1NZv4dL

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