Aspirin and its

binding sites
Week 3-4
Chris Carson
 Overview

Acetylsalicyclic acid

NSAID

Result of ancient medicine

Original molecule salicylic

acid derived from willow
bark
Charles Frederic Gerhardt
treated salicylic acid with
acetyl chloride to first
form Acetylsalicyclic acid
Source: 1,2
 Function- Introduction

Treats pain, fever, and inflammation.

Decreases risk of further damage after heart
attacks

Mechanism
Just beginning to be understood

Blocks a central process

Prostaglandins

Source: 1
 Prostagladins
Hormones used to carry local
messages
Created by Cells
Surrounding area activity
Control many processes
Constriction of muscle cells
around blood vessels
Blood clotting- Aggregation of
platelets
Labor- Constriction of uterus
Deliver & Strengthen Pain
signals
Induce inflammation
Created by cyclooxygenase
Source: 1
 Targets - Cyclooxygenase
Enzyme (COX)
Responsible for performing
first step in Prostaglandin
creation.
2 Types:
COX-1
Ubiquitous in cells
Create prostaglandins for basic
housekeeping messages
COX-2
Special cells only
Signaling pain and
inflammation

Source: 1, 3
 Aspirin and COX

Aspirin targets both

COX-1 & COX-2
Aspirin attacks and
inhibits that active site
Prevents the binding of
arachidonic acid to
active site preventing
production of
prostaglandins
Source: 1,2
 How does it do this?

Aspirin connects acetyl group to

serine amino acid
Permanent inactivation of enzyme
Acetylation of OH group in Serine

Active site buried deep inside

protein
Accessed by a tunnel in the middle
of the knob
Salicylic acid becomes bound nearby

Chimera 1PTH

Source: 2
 COX-2

Aspirin induces
conformational change in
low doses
Prostaglandin syntheses
to R-lipoxygenase
Initiates biosynthesis of
endogenous analogues of
Lipoxin
Lipoxins anti-
inflammatory eisosanoids
Source: 4
Aspirin-triggered
lipoxins

Source: 5
 Additional Effects

Uncouples oxidative phosphorylation in

cartilaginous mitochondria
Acts as a proton carrier into the mitochondrial
matrix where it ionizes to release protons
acting as a ATP synthase competitor

Induce the formation of NO-radicals in

body, reducing inflammation. (Breakdown of
lipoxins)
Questions?
 Works Cited
[1] https://pdb101.rcsb.org/motm/ 17

[2] Jeffreys, Diarmuid (2008).

Aspirin the remarkable story of a wonder drug. Bloomsbury Publishing USA
[3] Tirunagari SK, Derry S, Moore RA, McQuay HJ (2009).
"Single dose oral etodolac for acute postoperative pain in adults".
The Cochrane Database of Systematic Reviews (3): CD007357 .
[4] Gronert, Karsten et al. Selectivity of Recombinant Human Leukotriene D4,
Leukotriene B4, and Lipoxin A4 Receptors with Aspirin-Triggered 15-Epi-LXA4 and
Regulation of Vascular and Inflammatory Responses. The American Journal of Pathology
158.1 (2001): 39. Print.
[5] http://themedicalbiochemistrypage.org/ aspirin.php

[6] Somasundaram, S., S; et al. (2000). "Uncoupling of intestinal mitochondrial oxidative

phosphorylation and inhibition of cyclooxygenase are required for the development of
NSAID-enteropathy in the rat". Aliment Pharmacol Ther. 14 (5): 639650.
[7] Paul-Clark, M. J.; Van Cao, T; Moradi-Bidhendi, N; Cooper, D; Gilroy, D. W. (2004).