Nicotine as Drug Target: A

Chemoinformatics Approach

Kapil Jain (B.Pharm., M.S.(Pharm.))

Editorial Consultant
Outline
Introduction-History/Numbers

Nicotine Pharmacotherapy

Nicotine PK/PD

Nicotine Pharmacology

nACHRs Topology

NDD
Introduction
 Leaves of Nicotiana tobacum
cured and (usually) smoked

 Indigenous to North America

 Smoked by natives for

medicinal, ceremonial
purposes (~1 B.C.)

 Highly dangerous and

addictive

 Contains over 4000 chemicals

and 50 carcinogens
Pharmacotherapies
 other drugs
 Zyban (buproprion) – approved in 1997 for
smoking cessation
 originally an antidepressant (Wellbutrin)
 mechanism of action not well understood

 weak inhibitor of dopamine and noradrenaline

reuptake, and has also been shown to antagonize
nicotinic acetylcholine receptor function.
HISTORY
 Jean Nicot de Villemain
introduced tobacco to France,
promotes importation and
cultivation (1556)
 Chewed recreationally, used for
ailments (e.g. headaches, colds)
in Europe (1500s)
 Tobacco becomes major cash
crop of American colonies,
spurring demand for slave labor
(1600s)
NUMBERS
Half users
killed

~1.1
Kills ~7
billion
million
lives in
(world
LIC and
wide)
MIC Tobacco

~1 million ~6 million
(second- (direct
hand tobacco
smoke) use)
PHARMACOTHERAPY
FIRST-LINE PHARMACOTHERAPY
Nicotine Replacement Therapy
 Patch
 Gum
 Lozenge
 Inhaler
 Nasal spray
Non Nicotine Replacement
 Bupropion (Zyban)
 Varneciline (Chantix)
PHARMACOTHERAPY
NICOTINE PK/PD
NICOTINE PK/PD

Pharmacokinetics
Effects of the body on the drug
 Absorption
 Distribution
 Metabolism
 Excretion

Pharmacodynamics

Effects of the drug on the body

NICOTINE ABSORPTION

Absorption is pH dependent
 In acidic media
 Ionized  poorly absorbed across membranes
 In alkaline media
 Nonionized  well absorbed across membranes
 At physiologic pH (7.3–7.5), ~31% of nicotine is
unionized

At physiologic pH,
nicotine is readily absorbed.
NICOTINE DISTRIBUTION

 Nicotine in smoke peaks in brain very rapidly, despite

relatively slow increase in blood concentration

 A typical cigarette contains 20 mg of nicotine

 ~2.5 mg of nicotine is absorbed

 Half-life: ~ 2 hours

 Readily cross BBB in ~7 secs

NICOTINE METABOLISM

H 10–20%
excreted
N unchanged
in urine
N CH3

70–80% ~ 10% other

cotinine metabolites

Metabolized
and excreted
in urine
NICOTINE PHARMACODYNAMICS

Nicotine binds to receptors

in the brain and other Central nervous system
sites in the body.
Cardiovascular system
Exocrine glands

Gastrointestinal system
Adrenal medulla

Other:
Neuromuscular junction
Sensory receptors Peripheral nervous system
Other organs

Nicotine has predominantly stimulant effects

 NICOTINE
PHARMACOLOGY
NICOTINE PHARMACOLOGY
 Nicotine is a direct agonist
for nicotinic ACh receptors
 Nicotine initially causes a
rapid release of
adrenaline, the "fight-or-
flight" hormone
 Nicotine activates the
dopamine reward pathway
in the brain, which
reinforces continued
tobacco use
BIOLOGY of NICOTINE ADDICTION:
ROLE of DOPAMINE

Nicotine addiction
is not just a bad habit.

Discontinuation leads to
withdrawal symptoms.
nAChRs TOPOLOGY
IMPORTANCE of nAChRs

Alzheimer's

Schizophrenia
 NICOTINE RECEPTORS TOPOLOGY
Each NT can activate diverse receptors
e.g. acetylcholine can activate 2 classes of
receptors, nicotinic or muscarinic
Nicotinic AChR Muscarinic AChR
• Mimicked by nicotine • Mimicked by muscarine
(agonist) (agonist)
• Blocked by antagonists like • Blocked by antagonists
α-bungarotoxin like atropine
• Only in certain tissues • Cardiac muscle,
(skeletal muscle, parts of the cholinergic synapses of
CNS and PNS) the CNS
 NICOTINIC ACETYLCHOLINE
RECEPTORS (nAChR)
Ligand gated ion channel
Pentamer
α and β subunits
Twelve known subunits α 2-10
and β2-4
Two main types present in brain
o α7 nAChR subtype
High affinity for α-
bungarotoxin
o α4β2 nAChR subtype
High affinity for nicotine
Believed to upregulate in
response to nicotine
Architecture of α4β2 Nicotinic Receptor
α4β2 NICOTINE INTERACTIONS
Top
V111, F119
Loop E
W156
Loop B

L121
Loop E

Vicinal Cys, Y197, Back

Front Y204
Loop C

Y100 W57
Loop A Loop D
Base
α4β2 BINDING SITE
α4β2 nAChR Compounds in Clinical
Development for CNS Disorders
Compound Primary Indication Receptor Subtype Selectivity
Varenicline Smoking Cessation α7 (full agonist), α4β2 (partial agonist)
Dianicline* Smoking Cessation α4β2 (partial agonist)
Lobeline Smoking Cessation α4β2 (partial agonist)
ABT-089 Cognitive Dysfunction α4β2 (partial agonist)
TC-1734* Alzheimer’s Disease (α4β2)2β2 (full agonist), (α4β2)2α4
(partial agonist)
TC-5214 Depression α4β2 (antagonist)
S-38232* Alzheimer’s Disease α4β2 (full agonist)
BT-594 Pain α4β2 (full agonist)
*trial discontinued
NICOTINE DRUG DESIGN
NICOTINE DRUG DESIGN

The soul purpose of nicotinic drug design is

the management of nicotine dependence
(tobacco smoking) and for improvement of
cognitive deficits associated with
neurological and psychiatric disorders
DRUG DESIGNING

 Drug designing, is the inventive

process of finding new medications
based on the knowledge of a
biological target
 Designed molecule should be
 Organic small molecule
 Complementary in shape to the
target
 Oppositely charge to the
biomolecular target
DRUG DESIGNING

 Designed molecule will:

 Interact with Target
 Bind to target
 Activates or inhibits the
function of a biomolecule
such as protein
IN SILICO DRUG DESIGN

 In Silico drug designing is defined as the

identification of the drug target molecule by
employing bio/chemoinformatics tools

Structure
Based
In Silico
Drug Design
Ligand
Based
IN SILICO DRUG DESIGN
STRUCTURE BASED LIGAND BASED
 Know receptor  Don’t know receptor
 Don’t know ligands  Know ligands

What will be happy in there

 Protein/ligand interactions
 Biophysics/Docking  Statistical analysis of
what groups are
important for activity
In Silico Methods in Drug Discovery

 Molecular docking

 Virtual High through put screening

 QSAR (Quantitative structure-activity relationship)

 Pharmacophore mapping

 Fragment based screening

 TARGETS FOR
NICOTINE DRUG DESIGN
NICOTINE DRUG DESIGN

 Compounds with diverse structural features potentiate nAChRs

 Multiple PAM recognition sites proposed
 Pockets at the extracellular canonical (agonist-binding)
and non-canonical subunit interfaces
 Transmembrane domain of a single subunit
 Interface between adjacent subunits and
 Subunit's extracellular C-tail
 PAMs provide potentially selective modulation of a
subpopulation of nAChRs
NICOTINE DRUG DESIGN

 Constituents in cigarette smoke are MAO (A and B)

inhibitor
 MAO inhibition may assist smokers in quitting
 Inhibition of nicotine metabolism
 Clinical study with Methoxsalen (CYP2A6 inhibitor)
reduced smoking
SUMMARY

 nAChRs are transmitter (ACh)-gated ion channels

 five homologous or heteromeric subunits (α2-α10 and
β2-β4)
 α4- and β2-containing nAChR subtype mediate the
addictive effects of nicotine
 important for neuronal survival and maintenance of
cognitive performance and learning during ageing
 In Silico/CADD tools can be used for developing novel
and safe therapeutics
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THANK
YOU