Aromatase is the enzyme responsible for estrogen biosynthesis. Aromatase inhibitors (AIs) work by blocking the aromatase enzyme, thereby reducing estrogen production in postmenopausal women and inhibiting the growth of hormone receptor-positive breast cancer cells. Common AIs include anastrozole, letrozole, exemestane. Pharmacophore modeling is used to identify the chemical features responsible for a drug's binding and action. Molecular docking further elucidates the binding mode between aromatase inhibitors and the aromatase enzyme.

2. AIs

3. 1-Introduction:
1. What is the Aromatase Enzyme?
Aromatase, also called estrogen synthase, is
an enzyme responsible for a key step in the biosynthesis
of estrogen.
Increase Breast
cells

4. 1-Introduction:
2- What are Aromatase inhibitors?
• Aromatase inhibitors stop the production of estrogen in
postmenopausal women.
• Aromatase inhibitors work by blocking the enzyme
aromatase, which turns the hormone androgen into small
amounts of estrogen in the body.
• This means that less estrogen is available to stimulate the
growth of hormone-receptor-positive breast cancer cells.

5. 2-M.O.A of drugs

6. 2-M.O.A of drugs
Inhibit Aromatase Enzyme so stop turning androgen
into estrogen

7. 3-Drugs used as AIs:
Arimidex
Femera
Teslac
Aromasin

8. LetrozoleAnastrozole
Arimidex Femera

9. 4-SAR:
• Nitrogen-containing structures like the imidazoles
and the triazoles bind to the iron in the heme moiety.
• Cyano benzyl is important for activity.

10. 5-Uses:
AIs can be used In:
1. stop the production of estrogen in postmenopausal
women.
2. Gynecomastia.
3. Unexplained female infertility.

11. 6-Pharmacophore modeling:
1. What is the Pharmacophore modeling?
• The group of atoms in the molecule of a drug
responsible for the drug's action and binding with
receptor.
• The identification of a pharmacophore is important step
in understanding the interactions between a receptor
and a ligand.

12. • The training set aromatase inhibitors (anastrozole, letrozole,
fadrozole, vorozole) are represented as the best fit alignment to the
model.
• This training set is with low energy conformations of second and
third generation aromatase inhibitors and used these molecules to
generate a common-features pharmacophore

13. • Basic physicochemical features of known antiaromatase compounds
include a high degree of hydrophobicity and the potential to
establish hydrogen bonds as acceptors.
• The program found six possible alignment solutions displaying three
or four pharmacophoric points. The first two top ranked solutions,
HYP1 and HYP2, had four features, two hydrophobic groups, and
two hydrogen bond acceptors.

14. • Common-features (Catalyst /HipHop) pharmacophore
model of azole non-steroid aromatase inhibitors.
• The pharmacophoric query had four features: two hydrogen
bond acceptors (HBA1 and HBA2, green) and two
hydrophobic groups (HYD1 and HYD2, cyan).

15. 7-Doking:
What is the Doking?
Molecular docking was performed to elucidate the binding
mode of aromatase and its inhibitors.

16. • AutoDock Tools was used to prepare the molecules and
parameters before submitting it for docking analysis with
AutoDock
• To evaluate the validity of the docking system, the bound
substrate was removed from the crystallized structure of
aromatase and re-docked to the enzyme.
• Results indicated that the X-ray crystallography conformer
was nearly identical to the docked conformer, as deduced
from superimposition of the two structures that displayed
an RMSD of 1.350 Å. Moreover, the superimposed binding
pose of androstenedione