PHSC 5100 Fall 2018

CONCEPTS IN PHARMACEUTICAL SCIENCE

Principles of Medicinal Chemistry–III

 Drug developing targeting enzymes

November 29, 2018

Raymond G. Booth, PhD, RPh

211-B Mugar Hall
Ra.booth@neu.edu
 Lecture Schedule
9. Nov. 1 Pharmacokinetics (Dr. Kabadi)

10. Nov. 8 Medicinal Chemistry I

11. Nov. 15 Medicinal Chemistry II

Nov. 22 Thanksgiving Holiday, no class

12. Nov. 29 Medicinal Chemistry III

13. Dec. 6 Principles of Toxicology (Dr. Lin)

14. Dec. 13 FINAL EXAM (40% of Course Grade)

(Covers lectures 9-13)
 Medicinal Chemistry 1-III Required Reading
Drug Development Targeting Enzymes
1. Enzymes involved in oxidative stress
(e.g., MAO and COMT for Parkinson’s disease)
Reading: Foye’s Medicinal Chemistry chapter (posted)

2. Serine proteases
(e.g., acetylcholinesterase for Alzheimer’s disease)
Reading:
Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e
Laurence L. Brunton, Randa Hilal-Dandan, Björn C. Knollmann
Section II: Neuropharmacology
Chapter 9: Muscarinic Receptor Agonists and Antagonists
Chapter 10: Anticholinesterase Agents
https://accesspharmacy-mhmedical-com.ezproxy.neu.edu/Book.aspx?bookid=2189#165936889

Drug Development Targeting GPCRs

Reading: Dr. Loring’s lectures, journal articles (posted),
Chapter 3 in Goodman and Gilman
 COMT is a Phase II Drug Metabolism Enzyme
Catechol-
O-MethylTransferase
COMT HMT Sulfotransferases

TPMT
Glutathione-
S-Transferases
GST-A
Uridine
Glucuronosyl- GST-P
S-Transferases GST-T
GST-M

HMT: histamine methyltransferase;

TPMT: thiopurine methyltransferase; Evans and Relling, Science (1999)
X X
Warning: hepatotoxicity
Mechanism of Action
 A Molecular View of Dopamine Neurotransmission

tyrosine

Dopamine
neurotransporter dopamine

Postsynaptic
Dopamine
Receptors

Response
(movement)
A Molecular View of Dopamine Neurotransmission
Parkinson’s Disease
tyrosine

Postsynaptic
Dopamine
Receptors

Response
(movement)
 Catecholamine Biosynthesis
NH2 HO NH2
Tyrosine
COOH DOPA
Hydroxylase COOH
HO HO Decarboxylase
Tyrosine DOPA
HO NH2

HO
DOPA Decarboxylase = Dopamine
Aromatic Amino Acid Decarboxylase
DA beta-
hydroxylase

Norepinephrine
 Catecholamine Biosynthesis
NH2 HO NH2
Tyrosine
COOH DOPA
Hydroxylase COOH
HO HO Decarboxylase
Tyrosine DOPA
HO NH2

DOPA Decarboxylase =
HO
Aromatic Amino Acid Decarboxylase Dopamine

DA beta-
hydroxylase

Norepinephrine
 Other Human Phase I Enzymes of Drug Metabolism

CYP2D6
CYP2E1
CYP2C19

CYP2C9
CYP2C8
CYP2B6
CYP2A6
CYP1B1
CYP3A4/5/7 CYP1A1/2

Others (MAO)

Esterases/amidases (hydrolases)
ALDH These represent a relatively large
ADH amount of drug metabolism contribution

CYP: cytochrome P450, NQ01: NADPH:quinone oxidoreductase; DPD: dihydropyrimidine

dehydrogenase; ADH: alcohol dehydrogenase; ALDH: aldehyde dehydrogenase
Evans and Relling, Science (1999)
 Inhibitors of the esterase (hydrolase) Acetylcholinesterase for
Alzheimer’s Disease
Clinical: Cerebral Cortex
Deficits in cognition Frontal, temporal, parietal, occipital lobes.
Loss of: memory, visuo- Sensory and motor integration, vision, hearing,
spatial skills, language skills memory, consciousness

Neuropathological:
Degeneration of cortex neurons
Senile plaques: accumulation
of -amyloid protein and
neurofibrous tangles

Neurochemical:
Deficiency of ACh in cortex.

Etiology:
Unknown
Acetyl-CoA Choline

Acetylcholine
Acetyl-CoA

Acetylcholine
Acetylcholine
Much faster!!
 Structure of Acetycholinesterase
Cationic substrates are not bound by a negatively charged amino acid in the anionic
site, but by interaction of 14 aromatic residues that line the gorge leading to the active
site
=
Molecular interaction of ACH with ACHase

e-
e-
e-
e-
e-
e-
e-
Molecular interaction of ACH with ACHase (part A)
Molecular interaction of ACH with ACHase (part B)
Molecular interaction of ACH with ACHase (part C)

Hydrolysis of ester
takes 0.2 milli-sec
Molecular interaction of ACH with ACHase (part D)

Choline Acetic acid

Regenerated
enzyme
Acetylcholinesterase is a hydrolase that uses serine instead of water
Tx of Alzheimer’s disease with Ach-ase inhibitors
Symptomatic (increase ACh transmission)
3 classes of ACh-ase inhibitors:

1. Competitive inhibitors that recognize aromatic amino acid binding

pocket of AChase (bind via - electron stacking).
Donepezil
O
C H 3O
N
C H 3O

Tacrine
NH2

N
Tx of Alzheimer’s disease with Ach-ase inhibitors
Symptomatic (increase ACh transmission)
3 classes of ACh-ase inhibitors:

1. Competitive inhibitors that recognize aromatic amino acid binding

pocket of AChase (bind via - electron stacking).
Donepezil
O
C H 3O
+ H
N
C H 3O

Tacrine
NH2

N
Molecular interaction of ACH with ACHase

e-
e-
e-
e-
e-
e-
e-
 +

Although the tertiary piperidine nitrogen atom is sufficiently ionized at physiological pH, the unionized
form may also interact with the enzyme.
2. Mechanistic-based semi-reversible inhibitors: recognize serine protease binding pocket of
AChase and go through same hydrolysis reaction as ACh, but, the reaction is much slower
(15 minutes for pyridostigmine vs. 0.2 milli-secconds for ACh).

Rivastigmine
(Exelon)
Molecular interaction of Rivastigmine (protonated at physiological pH) with ACHase

38
Molecular interaction of Rivastigmine (protonated at physiological pH) with ACHase

e-
e-
e-
e-
e-
e-
e-
 Molecular(protonated
Molecular interaction of Rivastigmine interaction of ACH with
at physiological ACHase
pH) with ACHase (part A)
 Molecular(protonated
Molecular interaction of Rivastigmine interaction of ACH with
at physiological ACHase
pH) with ACHase (part B)
Molecular interaction of Molecular interaction
Rivastigmine (protonated of ACH with
at physiological ACHase
pH) with ACHase (part C)
 Molecular(protonated
Molecular interaction of Rivastigmine interaction of ACH with
at physiological ACHase
pH) with ACHase (part C)

H H
O Hydrolysis of amide
.. takes 15 min
For comparison: Molecular interaction of ACH with ACHase (part C)

Hydrolysis of ester
takes 0.2 milli-sec
 Acetylated vs. carbamylated Achase

r
Acetylated vs. carbamylated Achase