Department of pharmaceutical chemistry

Faculty of Pharmacy
Drug Design (DD-554)

Interactions of NSAIDs with COX-1 and

COX-2

‫عبدهللا محمود رجب عبدالرحمن‬

ID number: 142
 Introduction:
 Cyclooxygenase (COX) is an enzyme that helps create prostaglandins. Prostaglandins are natural chemicals in
the body that are vital to creating inflammation. High levels of prostaglandins are present in areas of the body
that become inflamed. They contribute to the initial phase of inflammation — called acute inflammation —
where symptoms like redness, swelling, and pain can be seen and felt.
 Prostaglandins are made from a chemical called arachidonic acid (AA). AA is a type of fatty acid in the body.
Fatty acids are the building blocks of fats, and are necessary for our body to function. COX is the enzyme that
converts AA to prostaglandins.
 COX is also responsible for converting arachidonic acid to thromboxane A2 (TxA2). TxA2 signals to our
platelets when it’s time to form a clot. It’s also a vasoconstrictor, meaning it narrows our blood vessels.
 This first step in creating TxA2 is converting arachidonic acid to prostaglandins. Then another enzyme —
thromboxane A2 synthase — changes prostaglandin to thromboxane. But not all COX enzymes can carry out
this process. It only happens with a type called COX-1.
COX-1 COX-2
Roles  COX-1 is generally considered a  In the CNS COX-2 is also constitutively
“constitutive” enzyme. This means that expressed, mainly in hippocampal and cortical
it’s produced in the body regularly, glutamatergic neurons where it has a pivotal role
regardless of whether we’re healthy, in synaptic activity, long-term synaptic plasticity
sick, or injured. Our bodies make it no and in the neurovascular coupling during
matter what. functional hyperemia.
 COX-1 is involved in many processes,
including:
o Joining platelets together in the
blood to stop bleeding (platelet
aggregation)
o Helping facilitate blood flow in the
kidneys
o Protecting your stomach lining
 As mentioned above, COX-1 is also
responsible for helping to create TxA2.
Too much TxA2 can be a problem —
it plays a role in causing heart
attacks, stroke, and high blood pressure
(hypertension).
Disorders  Owing to its predominant localization  COX-2 is mainly induced in response to
in microglia, COX-1 might be the inflammatory stimuli.
major player in neuroinflammation

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 Diclofenac Ibuprofen Celecoxib

Class NSAIDs (non selective COX inhibitors) NSAIDs (selective COX-2

inhibitor)
MOA  Work by inhibiting the cyclooxygenase (COX) enzymes,  A highly selective
which convert arachidonic acid to prostaglandin H2 reversible inhibitor of the
(PGH2). PGH2, in turn, is converted by other enzymes to COX-2 isoform of
several other prostaglandins (which are mediators of pain, cyclooxygenase,
inflammation, and fever) and to thromboxane A2 (which celecoxib inhibits the
stimulates platelet aggregation, leading to the formation of transformation of
blood clots). arachidonic acid to
prostaglandin precursors.
Therefore, it has
analgesic and anti-
inflammatory properties.
Uses  Used for treating pain, fever, and inflammation. This includes painful menstrual periods,
migraines, and rheumatoid arthritis.
Side  Common side effects include heartburn and a rash. May  Common side effects
effects have other side effects such as gastrointestinal bleeding. It include abdominal pain,
increases the risk of heart failure, kidney failure, and liver nausea, and diarrhea.
failure. Serious side effects may
include heart attacks,
strokes, gastrointestinal
perforation,
gastrointestinal bleeding,
kidney failure, and
anaphylaxis.
 Use is not recommended
in people at high risk for
heart disease.

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 Methods:
1. First, we have to draw the structures of the compound on MOE and to make sure that the
structures are correct u can select Compute 2D Molecules.

2. Then click File New Database. Select the location of your database and name it. You must
type .mdb at the end of the file to make it portable to MOE once again.

3. When you draw the structure of the desired

compound you have to do the following steps:
a. Select all the atoms of the drug then click
Minimize to reduce the energy to the least
possible.
b. In the database you created click Edit  New 
Entry  OK

 Diclofenac structure

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 Ibuprofen structure

 Celecoxib structure

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 4. Then, open protein data bank PDB and search for proteins with ligands that have the following
criteria:
a. From Human source, Homo sapiens.
b. Resolution 2A or smaller
c. R, Rfree 0.5 or smaller
So, I decided to choose these proteins (4O1Z and 6BL4) download them as PDB format.
o 4O1Z: Crystal Structure of Ovine Cyclooxygenase-1 Complex with Meloxicam
o 6BL4: Crystal Complex of Cyclooxygenase-2 with indomethacin-ethylenediamine-dansyl
conjugate
5. Open 4O1Z Protein in MOE
a. To do a semi flexible docking you need at first to select the whole protein then prepare the
protein for docking by clicking Compute  Prepare  Quick Prep
b. Select Sequence
c. This window will appear, make sure that synchronize button is checked, then select the drug in
this case is Meloxicam MXM.

6. Keep the selection held, Compute  Dock 

a. Change the site to be Selected Atoms.
b. Change the ligand to be MDB File and choose your data base.
c. Change the Poses to 5 and 3
d. Name the output and put .mdb at the end
e. Click Run
After you finish docking this data base window will appear showing the number of compounds with its
energy

 Results:
o Diclofenac (1) shows the least energy required
= -6.5371
o Pose 1 shows the best docking.

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 Conclusion
Drug 1 (Diclofenac) pose number (1) shows least energy required for docking so, it has the most stable
binding with enzyme.

 After doing the same methods with 6BL4 (Crystal Complex of Cyclooxygenase-2 with indomethacin.)
 After you finish docking this data base window will appear showing the number of compounds with its
energy
 Results:
o Celecoxib (3) shows the least energy required = -6.6075
o Pose 1 shows the best docking.

 Conclusion
o Drug 3 (celecoxib) pose number (1) shows least energy required for docking so, it has the most
stable binding with enzyme.
o From dockig of drugs with both enzymes we conclude that Celecoxib has a higher selectivity
towards COX-2 enzyme while Diclofenac and Ibuprofen have almost the same affinity towards
COX-1 and COX-2 so they are non seslective.

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 References:
1) "Celecoxib (Celebrex) Use During Pregnancy". Drugs.com. 4 May 2020. Archived from the original
on 25 January 2021. Retrieved 5 May 2020.
2) ^ "Celebrex 100mg capsule - Summary of Product Characteristics (SmPC)". (emc). 13 January 2020.
Archived from the original on 6 August 2020. Retrieved 5 May 2020.
3) ^ Jump up to:a b c d e f g h i j "Celebrex- celecoxib capsule". DailyMed. 31 May 2019. Archived
from the original on 24 February 2021. Retrieved 5 May 2020.
4) "Celecoxib (Celebrex) Use During Pregnancy". Drugs.com. 4 May 2020. Archived from the original
on 25 January 2021. Retrieved 5 May 2020.
5) ^ "Celebrex 100mg capsule - Summary of Product Characteristics (SmPC)". (emc). 13 January 2020.
Archived from the original on 6 August 2020. Retrieved 5 May 2020.
6) ^ Jump up to:a b c d e f g h i j "Celebrex- celecoxib capsule". DailyMed. 31 May 2019. Archived
from the original on 24 February 2021. Retrieved 5 May 2020.

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