Medicinal Chemistry

CHEM3407 /CHEM3410 & BPHM3015

Hongzhe SUN
Chemistry, HKU
2nd Semester, 2015

Whats Medicinal Chemistry?

The chemical principles of drug design & drug action and uses, drug
discovery and latest developments with case studies

Chemistry

Structural
biology

Medicinal Chemistry

Molecular
biology
Pharmacy
Pharmacology

Concepts & principles

What will we learn in Medicinal Chemistry?

1.
2.
3.
4.
5.
6.
7.
8.

Drug targets
Drug-target interactions
IC50, EC50, ED50, Kd
Enzyme inhibition: inhibitors
Transition-state inhibitor
Lead Optimization
ADME; SAR
Lipinskis Rule of Five

Course Requirement

Case studies

Medicinal Chemistry

Course work assessment (25%)

(i) 2 assignments, (ii) 1 short quiz
(iii) 2 day lab demonstration tours + 1 lab tour report
(iv) 1 oral presentation or 1 reading report on one selected
topic in medicinal chemistry

8-10 min oral presentation about one of selected topics

- 2 tutorials
- 1 Final examination (75%)
4

Course Content

Medicinal Chemistry

1. General Introduction of Drugs Discovery, Design, Development

2. Drug Targets
3. Proteins as Drug Targets: Structural Proteins
4. Proteins as Drug Targets: Enzymes - Discovery of HIV Drugs
5. Lead Optimization
6. Nucleic Acids as Drug Targets
7. Pharmacokinetics (SAR), Drug Delivery and Drug Toxicity
8. Selected Example of Drug Development: Anti-cancer Drugs
10. Computer-Aided Drug Design; Quantitative Structure Activity
Relationship (QSAR)
11. Case studies
(Prof. Xuechen LI)

Useful References

1. An Introduction to Medicinal Chemistry (6e), G.L. Patrick, Oxford University Press, 2013
2. Medicinal Chemistry - An Introduction, G. Thomas, John Wiley, 2000
4. Drugbank: www.drugbank.ca (good website for more details of drugs) & PDB
5. Software: PyMOL (educational version molecular graphics display)
3. ISIS DRAW 2.14, CHEM DRAW, SYMYS DRAW (chemical structure drawings)

Medicinal Chemistry

1.

General Introduction

Top three diseases in 2009 (World Health Organization (WHO))

Heart Disease, Cancer & Stroke ( )
Global Infectious diseases in 2008-2009:
Malaria ()
Tuberculosis ()
Measles ()
(WHO statistics report 2010: http://www.who.int/whosis/whostat/2010/en/index.html)

Virus infection:
Human immunodeficiency/Hepatitis B, C virus (HIV, HBV & HCV)
Severe acute respiratory syndrome (SARS)
Avian influenza (bird flu)
Swine flu

Human Life span?

Era
(approx. period)
Neanderthal (over 130,000 yrs ago)
New Stone Age (9500 BC 2000 BC)
Ancient Rome (753 BC AD 1453)
Medieval England (AD 1066 1337)
End of 18th Century
Early 20th Century
1940s
Current

Average Lifespan
(years)

Longevity increases since 19 century. . .

Drug Discovery Design & Development ! (4Ds)
Future?

The World's 10 Best-Selling Drugs

Trade name
Producer
Sales (billion$)
Lipitor (cholesterol)
Pfizer
12.5
Plavix (blood thinner)
Bristol-Myers
5.9
Nexium (heartburn )
AstraZeneca
5.7
Advair (asthma inhaler)
GSK
5.6
Zocor ( high cholesterol)
Merck
5.3
Norvasc ( high blood pressure)
Pfizer
5.0
Zyprexa (mental disorder)
Eli Lilly
4.7
Risperdal (mental disorder) Johnson & Johnson 4.0
Prevacid ( acid production
Abbott
4.0
in stomach)
Effexor (anti-depressant)
Wyeth
3.8
http://www.forbes.com/2006/03/21/pfizer-merck-amgen-cx_mh_pk_0321topdrugs.html

Medicinal Chemistry

What is a Drug?

a drug is any absorbed or applied substance that change our

physiological or psychological functions in the body such as
digestion, blood circulation, wound repair, etc. Drug should
be administrated so as to cures or prevents illness caused
Every substance has a potential of being a drug, depends on the
patient, type of illness, desired effect, dose given, etc.
Medicinal drug? Street drug? Social drug?
CH3 CO2CH3
N
H
O

aspirin

cocaine ()

nicotine in tobacco

alcohol in wine

Types of Medicinal Drugs

1. herbal drugs (isolated), i.e. traditional Chinese medicine (TCM)
2. synthetic drugs (man-made), i.e. aspirin from salicylic acid
3. mineral drugs (exploited), i.e. HgS (Cinnabar) & AsS (Realgar)
- modes of administration: oral, intravenous injection or external use
- target on disease-causing molecules (e.g. viral proteins, DNAs)
anti-viral, anti-fungal, anti-bacterial (anti-microbial),
anti-cancer, (mutated body tissues) etc
- target on biological functions in different organs (heart, lung, gut wall)
anti-pyretics, analgesic, anti-diarrhoeal , anti-arrhythmic , anticoagulant ,
anti-tussive , anti-perspirant ,
anti-arthriti etc

Where do drugs come from ?

1) Plants exacts: Taxol, Morphine, Quinine (structurally complex)

Taxol (anticancer)

Morphine (analgesic)

Pacific Yew ()

Opium (or Poppy)

Quinine (anti-malarial)

Barks of Cinchona tree

2) Animals (organs): Insulin (pancreas), Estrogen (ovaries)

3) Microorganisms: penicillin & tetracycline (serendipitous discovery)

Penicillin (antibiotic) - Penicillium mold

Tetracycline (antibiotic) Streptomyces

4) Chemical synthesis (pharmaceutical industry variety of products)

H3 N

Cl

Li2CO3
(Mood stabilizer/
Bipolar disorder)
HO

Pt
H3 N

HO
OH

Cl

Cisplatin (anti-tumor)
Aspirin

Famotidine (histamine H2-receptor antagonist

that inhibits stomach acid production)

O
O

Aspirin synthetic drug (analgesic,

antipyretic (), anti-inflammatory)
1st

Lipitor (inhibits HMG-CoA reductase in liver)

blood cholesterol

5) Gene splicing (recombinant DNA technology, i.e. peptide drugs)

Drugs Discovery, Design & Development

- in reality, over 10-year effort to develop 1-2 new safe and useful drug!

1 compound

Roadmaps for New Drug Development

Drug Discovery: Find a lead Compound

1) choosing a disease (what symptoms & causes?)
2) choosing a drug target (protein, DNA, genes, cells)
Molecular Biology biological phenomena at the molecular level through
the study of DNA and RNA, proteins involved in genetics and cell
functions. The goal is to identify molecular targets mainly by:
(i) Genomics study of the genomes & entire DNA sequence of organisms.
The goal is to identify disease-causing gene (or mutation)
(ii) Proteomics study of proteins, particularly their structures and
functions. The goal is to identify disease-causing protein or receptor, to
validate target identity.
(iii) Metabolomics study of metabolites (organics, amino acids, metal
ions) generated by cell, tissue, organ or organism, which are the end
products of cellular processes.

Medicinal Chemistry

Genomics

RNA sample
preparation

Sample
amplification &
labeling using PCR

Hybridize
sample to chip

Proteomics

Array reading &

data analysis
TGCAGTCAA
DNA sequence

His-Gly-Ala-Pro
Protein sequence
Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis

3) Choosing a suitable bioassay (protein, cell or animal-based?)

12

Science 1999, 286, 971-974

Key Q: which compound is medicinally or biologically active or

relevant? a discovery step based on a compound-based approach

Drug Discovery (Real Story 1)

Discovered the 1st arsenic
compound (Salvarsan) in 1909 to
cure syphilis
by screening many Ascontaining compounds, a useful
drug can be discovered (1st team
use chemical modifications to
find a lead compound) - a basis
for modern pharmaceutical
research

Salvarsan

Marketed in 1910, better than

mercury-containing drugs, due to
side effect, was supplanted by
penicillin in 1940.

Mechanism-based drug discovery

Problem: surgery, radiation, anti-cancer drugs have certain limitations
Molecular mechanism & (patho)physiology of cancer (new drug target)

new drugs (Nolvadex & Herceptin)

toward over-expressed HER-2
receptor of breast cancer cells
derived from genes BRCA1 and
BRCA2

cancer cell

inhibitor of enzyme or enzyme

receptor antagonist for cell-cycle
regulation, apoptosis, angiogenesis
and signal transduction of cancers
(details discussed later)
SCIENCE 2000, 287, 1969-1973

10

Mechanism-based drug discovery

- Human genome: ~ 30,000 genes as predicted for drug targets (~ 500)
- e.g. PDGF, EGF receptors as new anti-cancer drug targets

OH
HO

* PDGF (platelet-derived growth factor) & EGF (Epidermal growth factor)

Drug Discovery: Find a lead Compound!

4) making a set of compounds (library), and test them each to see
which one is significantly effective in the bioassay (screening)
and thereafter identify this as the lead compound
(a starting point for drug design)

5) synthesis, isolation, purification of the lead compound

(mostly contributed from modern organic, analytical chemistry)
6) identify and validate suspected binding site of lead-target
complex in molecular level (structural determination, e.g.
macromolecular NMR spectroscopy & X-ray crystallography)
solution vs. solid-state structures or dynamic vs. static structures

11

Drug Design: Lead Optimization

optimize lead-target (drug-target) interactions (both qualitative
and quantitative structure-activity relationship QSAR) via
systematic variations of the lead structure
optimize the leads access to the target (experimental data on
stability, solubility, bioavailability of drug)
sometimes bioinformatics, modeling and theoretical calculations
help to judge the experimental data
evaluate in vitro & in vivo activity? Lead-target selectivity?
pharmacokinetics & toxicity?

Medicinal Chemistry

Rational Drug Design (Real Story 2)

- Cimetidine: a chemical landmark for rational drug design
(1964) which change people's lives. James Black (Nobel Prize in 1988)
H
N

NH2
HN
N

Histamine ()

NH

N--guanylhistamine

- stimulates gastric juice release

upon binding to H1, H2, H3 & H4
receptors (histamine is agonist)*

H
N

S
N

H
N

H
N

HN
N

Burimamide

HN

NH2

HN

- 1st H2 antagonist, 100x more potent than

N--guanylhistimine in vitro, but inactive in vivo

H
N
N

NO2

N
H

N
H

Cimetidine (Tagamet)

S
O

* An agonist is a chemical that binds to a receptor of a cell and triggers a cellular response. Thus an agonist
causes an action, an antagonist blocks the action of the agonist

12

Nobel Prize in Medicine and Physiology

1988- The Nobel Prize in
Physiology or Medicine was
awarded jointly to Sir James W.
Black, Gertrude B. Elion and
George H. Hitchings "for their
discoveries of important
principles for drug treatment".
Sir James W. Black

Gertrude B. Elion
George H. Hitchings

1964-The Nobel Prize in Chemistry to Dorothy Crowfoot Hodgkin

"for her determinations by X-ray techniques of the structures of
important biochemical substances".

1945- The Nobel Prize in Physiology or Medicine jointly to Sir

Alexander Fleming, Ernst Boris Chain and Sir Howard Walter Florey
"for the discovery of penicillin and its curative effect in various
Dorothy C Hodgkin
infectious diseases.

Drug and Target Validation (Real Story 3)

R = PhOCH2

Penicillin
- by Fleming, Chain, Florey
discovery and its medicinal
properties in various infectious
diseases (Nobel Prize in 1945)

- X-ray structure solved by Dorothy Hodgkin in 1945

- Development of protein X-ray crystallography,
validates binding/active site, facilitates drug design

monomer

Co
Zn

- monomer binds to its receptor,

triggers polymerization of blood
glucose to glycogen in liver !
- polypeptide as drug, since
binding to receptor maintains
normal metabolism.
i.e. Insulin injection for diabetes

13

Drug Development (Clinical Development)

(drug development)

(drug discovery & design)

Pre-clinic testing

clinic testing (human being)

synthesis & purification

animal testing
New Drug

Phase I

toxicity
pharmacokinetics

Phase II
Phase III

Phase IV

improve manufacturing processes, cost,

formulation, shelf-live, stability in air,
humidity and temperature, etc.
post-market monitoring thereafter

Clinic Testing (What 4 phases?)

Pre-clinic testing passed

(new potent drug)

Phase I: healthy volunteers: bio-availability & bio-marker? (not applicable to anti-cancer drugs)
Phase II: patient: PIIa, smaller dose & open label, acute side-effect? & efficacy?
PIIb, efficacious dose & double-blind (remove bias/preference)
Phase III: more patients: large scale multi-center double-blind, statistical medical benefit,
efficacy over existing drug, long-term side-effect?
Drug appears in market after FDA approval!!!!
Phase IV: Post-market monitoring of any reported side-effect and related effectiveness

14

Medicinal Chemistry

2. Drug Targets
Cell Structure & Cell Membrane
Drug Targets Proteins & Nucleic acids
Cell Membrane Lipids
Carbohydrates
Intermolecular forces between drug and target molecules
a) Electrostatic or ionic bond
b) Hydrogen bonds
c) Van der Waals interactions
d) Hydrophobic interactions
e) Dipole-dipole/Ion-dipole/Induced dipole interactions

Cell Structure

Medicinal Chemistry

- Human, animal and plant cells

eukaryotic cells (true nucleus)
- nucleus contains genes
(DNA, blueprint for life)

- cells have high% fluid

(cytoplasm) covered
by cell membrane
- functional organelles
mitochondria, (power house)
Lysosome, Golgi (fat storage),
Ribosomes, endoplasmic reticulum
(biosynthesis of protein from DNA)

15

Medicinal Chemistry

Cell Membrane

- phospholipid bilayer & bound proteins (receptor & ion channel)

Polar head
Group
CH2CH2NMe3
O
O P O
O
CH2 CH CH2
O O
O O

Hydrophobic Tails

phospholipid
Medicinal Chemistrybilayer

Some Features of Drug & Targets

Target: large molecules (e.g. protein, DNA), drug is smaller in
size, at optimal conditions, bound and unbound target
molecules are in a dynamic/static equilibrium
Targets have binding sites, where drugs binds target by
several intermolecular bonds. The binding sites are typically
hydrophobic pockets or cavity or cleft near the surface of the
target molecule.
i.e. a functional group of a drug molecule involved in binding is
binding group, whereas a region of a target molecule involved in
binding is binding region
Usually a structurally flexible drug molecule binds different
targets resulting in side effects and binds more binding sites of
one target, leading to increase in medicinal activity.

16

When Drug binds Target

- drug-target binding sometimes might induce a shape/structural

change of binding site in order to accommodate the drug

Types of Drug targets

i) Proteins

Enzymes
Receptors
Carrier proteins
Structural proteins

ii) Lipids

Cell membrane lipids

Medicinal Chemistry

iii) Carbohydrates
Cell surface carbohydrates
(antigens and recognition molecules)
iv) Nucleic acids DNA & RNA
- most of these molecular targets are from pathogenic substances
(i.e. bacteria, virus, fungi, cancer cells, etc)

17

Drug Target - Cell Membrane Lipids

- drugs could be anesthetics () and antibiotics
i.e. amphotericin B (B) - antifungal agent

Drug Target - Cell Membrane Lipids

How drug kills fungi? (a) drains cells with H2O via polar tunnels or
b) disturbs cell metabolism by lowering intracellular K+ ions conc.

18

5 mM
[K+]
[K+]= 92 mM
[Na+]= 11 mM
[Cl-]= 4.2 mM

152 mM
[Na+]
120 mM
[Cl-]

Drug Target - Cell Membrane Lipids

Valinomycin: antibiotics
- contains D/L-Valine, D-hydroxyvaleric acid & L-lactic acid
ester

K+

amide

highly selective for K+ over Na+ ions (stability constant for the
K+-bound complex is ~106 and for the Na+-bound complex is 10).
K+-specific transporter
binding to cell membrane lipids depletes intracellular K+ across
cell membrane lipids, finally damage bacterial cells.

19

Membrane Bound Protein (ion Channel)

- regulate cellular K+/Na+ (or small molecules) uptakes

Drugs work on channels:

Ca2+ channel blockers: to treat high blood pressure
The entry of Ca2+ is critical for the conduction of the
electrical signal that passes from muscle cell to muscle cell of
the heart, and signals the cells to contract.
It also is necessary in order for the muscle cells to
contract and thereby pump blood.
In the arteries, the entry of calcium into muscle cells
causes contraction of the cells and thereby dilates (widens)
the arteries.

Dihydropyridine Ca2+ blocker

20

Medicinal Chemistry

Drug Target - Cell Membrane Lipids

Gramicidin A ( A): antibiotics against Gram-negative bacteria
- polypeptide with alternating L- & D- amino acids,
formyl-(L-X)-Gly-(L-Ala)-(D-Leu)(L-Ala)-(D-Val)-(L-Val)-(D-Val)-(LTrp)-(D-Leu)-(L-Y)-(D-Leu)-(L-Trp)(D-Leu)-(L-Trp)-ethanolamine

where X = valine or isoleucine

Y = tryptophan
Gramicidin A has 8 Trp residues.
head-to-head dimer solved by NMR.

- bactericidal activity due to the increased permeability of bacterial cell

membrane, that allows more H+ to travel via polar tunnels, destroying
the ion gradient between cytoplasm/extracellular environment.

Drug Target - Carbohydrates

- cell surface carbohydrates play important roles in cell recognition,
regulation and growth. They might be potential targets for the
treatments of certain bacterial and viral infections, cancer and
autoimmune diseases, as long as they are recognized as antigens
antibodies
Ceramide 'anchor'

Carbohydrate 'tag'
HO

SUGARS O

Carbohydrate 'tag'

HO

(CH2)12CH3

OH
Carbohydrates

pathogenic cell
membrane

(CH2)16CH3

HN

OH
Ceramide unit

O
HO
RO

HO
O

(CH2)16CH3

Fatty Acid (e.g. S tearic acid)

NH2
OH
HO
OH
Carbohydrate
OH
(R=various carbohydrate structures)
S phingosine
HO

(CH2)12CH3

- antigen-antibody binding triggers immune

Medicinal Chemistry
defense system to kill the bacteria or virus

21

Remarks on Drug-Target Selectivity

- High target selectivity of drug (i.e. towards a single target) could
reduce undesired side-effect
- High selectivity towards a group of disease-related targets (enzymes, or
receptors) could improve drugs efficacy (medicinal effectiveness)

- High selectivity between species (bacteria or virus) could enhance

its uniqueness being anti-bacterial or anti-viral agents
e.g. drug identify the target unique to the pathogen (bacterial cell wall)
or identify common targets with low homology (viral proteases)

- High selectivity among different organs/tissues (heart, lung or brain)

could reduce undesired side-effect

Bioassays evaluate the potentials of drugs

- in vitro (proteins or cells in test-tube) or in vivo (animal models)

pure protein-drug mixture

stained cell (or unstained)?

embryo of a fish dosed by drug

- simple, quick and closely related to medicinal relevance

(use a substance with anti-fungal properties, to kill cancer cells?)
- enables study of drugs biological activity (inhibition activity) &
screening for side-effects, cytotoxicity, pharmacokinetic profile, etc

22

Commonly-used Terms (in vitro bioassays)

- Affinity is a measure of how strong the drug binds to the receptor.
- Efficacy is a measure of the maximum biological effect (biochemical
event within the cell or a physiological event e.g. muscle contraction)
that a drug can produce. (note: high affinity of a drug high efficacy)
- Potency of a drug refers to the amount of drug required to achieve
a defined biological effect the smaller the dose required, the more
potent the drug. Thus potency relates to how effective a drug in the
cellular level and is the amount of drug required to produce 50%
of the maximum biological effect (i.e. EC50).
(note: a potent drug can have a low efficacy, i.e. low specificity)

Medicinal Chemistry

Medicinal Chemistry

Affinity, Efficacy and Potency

Dissociation constant, Kd (unit = nM or pM)
- determined by (i) isothermal titration calorimetry (ITC) (based on
enthalpy change) or (ii) NMR spectroscopy (based on integral ratios)

- at optimal condition, Kd equals to [Drug] if 50% of binding sites of

target occupied by the drug, where [Target] = [Target-Drug], thus a
smaller Kd means a higher affinity between drug and target

23

Isothermal Titration Calorimetry

time

Ligand (drug)

Protein

- measure the enthalpy change upon ligand (or drug)-protein binding

with reference to a control with no drug, to find Kd or Ka.
- experimental details and application (lab tour of MedChem)

Half maximal inhibitory concentration, IC50 (unit = nM)

- concentration of a drug required to inhibit 50% of the target activity,
(a measure of effectiveness of drug in inhibiting biological function)
where target activity: absorbance/luminescence, % cell death, etc
IC50 =5.5 M

24

Half maximal inhibitory concentration, IC50 (unit = nM)

- concentration of a drug required to displace half of the bound
ligand from a liganded target molecule
Drug + Protein-ligand complex

Protein-drug complex
(displacement assay)

A
B
IC50 = 0.05 nM

[drug]

Inhibitory Constant, Ki (unit = nM)

- concentration of a drug required to occupy 50% of the binding site
of the target in the absence of ligand (substrate)
- if drug & ligand L (e.g. substrate if target = enzyme) compete with
the same binding site of the same target, (competitive inhibition)

- at optimal condition,
[L] = Kd thus Ki = IC50/2 (independent of assay conditions)
- smaller Ki, higher inhibition activity of the drug

25

Half maximal effective concentration (EC50)

- concentration of a drug required to produce 50% of the maximum
possible effect after a specified exposure time
- a measure of drugs potency or efficacy, whereas IC50 is a measure
of drugs inhibition ability to a target, (50% inhibition in vitro)

1.0
Eobs/Emax

0.5

0.0

[Drug]

- smaller the EC50, more potent of the drug

- EC100 or Emax means efficacy

Severe Acute Respiratory Syndrome Coronavirus

(SARS-CoV) Helicase targeted by the drug HE602

ATPase

ATP

ADP + Pi

Structure of HE602 & image of SARS-CoV

HE602 inhibited ATPase activity of SARSCoV Helicase

X-ray structure of SARS-CoV Helicase

with an inhibitor CMK (PDB: 1uk4)

HE602 inhibited SARS-CoV plaque

formation (response) with EC50 of 6 M.

26

Helicase as a drug target for SARS CoV

Unwinds dsDNA to ssDNA (ds double strand, ss single strand)

dsDNA
ssDNA

Inhibition of SARS-CoV Hel (helicase) activity

by HE602 observed by polyacrylamide
electrophoresis (SDS-PAGE) of labeled duplex
and single-stranded DNA.

Control
0
0.25

[HE602]
0.5

1.0

2.5 M

Chem. Biol. 2004, 11, 1293

- HE602 inhibits helicase activity of SARS CoV, by suppressing

the unwinding process from dsDNA to ssDNA

in vivo bioassays
carried out on animals (mouse, fish, not
human being) or transgenic animals if the
required human receptor is absent in animals,
or a significant difference in affinity for drug
toward the human and animal receptor

Transgenic animal =
animal-human hybrid

measure a physiological effect (blood pressure, weight) upon

dosing
with a drug with known amount within a period of time
identify side-effect, such as behavioral and physiological disorders
human and animal have different bioavailability (how much drug
intact in bloodstream after taken) and metabolism, rationalization of
results is difficult as many factors involve to affect the outcomes.

27

Commonly-used Terms (in vivo bioassays)

Effective dose, ED50
-a measure of drug potency based on animal model
-amount of a drug (mg/kg) required to produce 50% of the
maximum therapeutic response
-correlated to IC50 in in vitro assays
ED90 - used in anti-cancer, anti-bacterial and anti-viral drugs

Medicinal Chemistry

Lethal Dose, LD50

- lethality due to a given substance or a type of radiation

- concentration of a drug required to kill 50% of test population
or a dose at which 50% of subjects was dead
-depend on type of animal model, and method of administration
i.e. a toxic substance inhaled or injected into the bloodstream usually
require a smaller lethal dose than if the same substance is swallowed.

28

Medicinal Chemistry

Maximum Tolerated Dose, MTD

- concentration of a drug causing a decrease of 20% in average
body weight of the test population

Therapeutic ratio or index

- ratio of the amount of a therapeutic agent that causes the therapeutic
effect to the amount that causes death. That is the lethal dose of a
drug for 50% of the population (LD50) divided by the minimum
effective dose for 50% of the population (ED50)
- a higher therapeutic index is preferable! i.e. a patient takes a higher
dose of that drug to reach the lethal threshold than the dose taken to
have the same therapeutic effect.
The larger the index, the better the drug!

Intermolecular Forces
Drug and target molecules interact to each other via following ways:
a) Electrostatic or ionic bond
b) Hydrogen bonds

c) Van der Waals interactions

d) Hydrophobic interactions
e) Dipole-dipole, ion-dipole,
induced dipole interactions

Binding site with drug-target interactions

29

Medicinal Chemistry

a) Electrostatic or ionic bond

- initial interactions to guide the drug molecule to enter binding site

- between groups of opposite charges (the strength of the ionic
interaction is inversely proportional to the distance between the
two charged groups)
- strongest intermolecular bonds (2040 kJ mol-1 per one bond)
- stronger interactions usually occur in hydrophobic environments,
why? (i.e. less charge dispersion by polar solvents)

Medicinal Chemistry

b) Hydrogen bonds

- +
X H
Drug

Y Target

HBD

HBA

Drug Y

HBA

+ H X

Target
HBD

- weaker than electrostatic interactions but stronger than van der Waals
- between an electron-deficient hydrogen atom (H-bond donor, HBD)
and an electron-rich atom (Y = N, O, S) (H-bond acceptor HBA),
but HBD must not be any C-H
- directional & vary in strength, depends on HY distance, XHY
(shorter HY distance and/or linear XHY strengthens H-bond)

30

b) Hydrogen bonds Classifications (520 kJmol-1 per one bond)

HBA
Strong: carboxylate (CO2-), phosphate (PO43-), tertiary amine (R3N+)
Moderate: carboxylic acid (RC=O(OH), amide (RNH(C=O)R)
ketone (R2C=O), ester R(C=O)OR, ether (ROR),
alcohol (ROH), water (H2O)
Poor:

sulfur (RSH or RSR), aromatic ring (C6H5),

amide nitrogen (RCO(NH)R), halides, amine (RNH2)

HBD
Strong:
quaternary ammonium ion (NH4+, RNH3+, R2NH2+)
Moderate: H2O

c) Van der Waals interactions

- weak interactions (25 kJmol-1)
- in hydrophobic region of drug and target molecules, due to
transient dipoles with higher and lower electron density
- strength of interactions drop off rapidly with increasing distance,
thus drug must be close enough toward binding region to form
such weak interactions.

Hydrophobic regions
+ -

Transient dipole on drug

DRUG
+

van der Waals interaction

Binding site

Medicinal Chemistry

31

d) Hydrophobic interactions
- strength <1 kJmol-1
- between non-polar surfaces, i.e. exposed hydrophobic regions of
drug and target that are not surrounded by solvents
- thermodynamically feasible due to the entropy-driven process
(S > 0) i.e. water molecules adhered on hydrophobic regions of
drug and target molecules escape upon hydrophobically interacted

Desolvation penalty
- polar regions of a drug and its target are always solvated prior to
forming any sort of interaction (or binding)
- partial or complete desolvation of drug is necessary, that requires
energy input or desolvation penalty (G > 0)
- total energy gained due to drug-target interaction (or binding) must
be greater than such energy input
H

O
H

O
R

C
R

C
R

Binding site

R
Binding site

Desolvation-Energy penalty

Binding site

Binding - Energy gain

-thus drug solubility in water is of a concern, not only drug efficacy,

bioavailability, but also excretion after body metabolism

32

e) Dipole-dipole interactions
- occur where a drug and the binding site of target have non-zero
dipoles, both dipoles self-align themselves, directing an unique
orientation of the drug molecule in the binding site
- the resulting orientation is beneficial if binding groups of drug are
positioned correctly with respect to the binding regions of target.
otherwise, it is detrimental
- strength of such weak interaction decreases with increasing distance
more quickly than that for electrostatic/ionic interactions
- O
+ C
R

Local molecular
dipole
R
localised
d ipole of target

Binding site

Binding site

Medicinal Chemistry

e) Ion-dipole interactions
- occur where the charge on drug molecule interacts with the dipole
moment of ionic residues (e.g. CO2- in Asp & Glu, -NH3+ in Arg &
Lys, -NH+ in His etc) of the target
- stronger than a dipole-dipole interaction, its strength falls off less
rapidly with distance than that for dipole-dipole interaction

R
C

O +

R
C
O
O

Binding site

O +

H3N

Binding site

33

Medicinal Chemistry

e) Induced dipole interactions

- occur where the charge on drug molecule induces a spontaneous
dipole moment on the pi-electron system, (e.g. phenyl ring in Phe,
indole ring in Trp) and quaternary ammonium ion is very common

34