Docking Studies of LTA4H inhibitors against

Colorectal Cancer
Presented by,
Jerin K Benny
Akshaya K V
Rijuta Pandey
 ◆ Introduction
◆ Target Protein - LTA4H
◆ Ligand - 6-Gingerol

Contents
◆ Library of Molecules
◆ Docking Result
◆ Synthetic Route
◆ Possible Metabolism
◆ Conclusion
 Colorectal Cancer
The what question!

◆ Cancer that starts in the colon or rectum

◆ Most are adenocarcinomas (cancers that begin in cells that make and release mucus and other fluids)
◆ Begins as a growth called polyp, which may form on inner walls of the colon or rectum
● Two types of polyps
○ Adenomatous polyps (adenomas) - Generally turn into cancers; so also called precancerous
condition
○ Hyperplastic polyps and inflammatory polyps: Generally not precancerous
◆ Metastasis
● Grows into the wall starting from inner mucosal layer
● Grows into blood or lymph vessel from walls and travels to different parts
 ◆ Low RBC Count
◆ Change in bowel habits, such as diarrhea,
Colorectal Cancer constipation, or narrowing of the stool, that lasts
for more than a few days
How does it show up? ◆ Rectal bleeding with bright red blood
◆ Blood in the stool
◆ Cramping or abdominal (belly) pain
◆ Weakness and fatigue
◆ Unintended weight loss
 ◆ Certain types of diet
● Red meat
● Meat cooked at high temperature
Colorectal Cancer ◆ Smoking
◆ Heavy Alcohol Use
◆ Personal history of Inflammatory Bowel
Risk Factors….?
Disease
◆ Genetic factors
◆ Obesity
◆ Physical Inactivity
 ◆ Fourth most common type of cancer
diagnosed in the US and around the globe

Colorectal Cancer ◆ Third leading cause of cancer-related

deaths in the US and tenth in India
◆ India’s low incidence rate is also
How bad…? associated with a low 5-year survival rate
(<40%)
● Late detection
● Lack of effective treatment
 ◆ Presence of K-ras oncogenes
Colorectal Cancer ◆
◆
Chromosomal Instability
Loss of 5q allele
◆ Loss of 8p allele
Biomolecular Markers
◆ Loss of 17p allele
◆ Loss of 18q allele
◆ Microsatellite instability
 ◆ Thymidylate synthase
◆ Dihydropyrimidine dehydrogenase

Colorectal Cancer ◆
◆
Thymidine phosphorylase
ERCC1 gene
◆ Topoisomerase I
Chemotherapeutic Targets ◆ Vascular endothelial growth factor
◆ Epidermal growth factor receptor
◆ Matrix metalloproteinase
◆ COX-2
 What are leukotrienes?
Class of structurally related paracrine hormones derived from oxidative metabolism of arachidonic acid.
Leukotrienes: Mediator of inflammation

ARACHIDONIC
ACID

LTA4

SPASMOGENIC PROINFLAMMATORY
LTC4 LTB4
 Leukotrienes and Colorectal Cancer

5 – lipoxygenase

Unstable epoxide LTA4

Arachidonic acid

LTA4 Hydrolase
INHIBIT IT!
Proinflammatory LTB4

• LTB4 ,a classical chemoattractant of human neutrophils and triggers adherence

and aggregation of leukocytes to vascular endothelium.
• It modulates immune responses.
• LTB4 participates in the host defence against infections.
Mechanistic pathway from
LTA4 to LTB4
 How LTA H is a culprit!
4

◆ A bifunctional zinc metalloenzyme .

◆ Also exhibits an anion dependent
aminopeptidase activity.
◆ Relevant target for cancer therapy.
◆ overexpressed in several cancer lines including
colorectal cancers.
◆ LTA4H is implicated in the anchorage
independent growth of HCT116 colon cancer
cells.
◆ It’s enzymatic product LTB4 is implicated in he
pathogenesis of several inflammatory diseases like
asthma, psoriasis, rheumatoid arthritis and bowel
Structure of LTA4H bound with 6- disease.
Gingerol
 6-Gingerol (Ligand)
◆A bioactive ingredient of ginger root.
◆Exhibits anti-inflammatory and antitumorigenic activities.
◆Effective in the suppression of the transformation, hyperproliferation, and inflammatory processes.
Synthesis of 6-Gingerol
 Interactions of 6-Gingerol
◆Hydrogen bonding between –OH in the phenyl ring of the ligand and hydrogen in the –NH2 group of LYS-565-
A
◆Pi-Pi stacking between tyrosine residue and ligands benzene unit.
 Library of molecules
Molecule Interactions
1 H-Bonding,1 Pi-Pi stacking
6-Gingerol

2 Pi-Pi stacking(Phenyl ring of the ligand & phenyl ring of TYR373A

& PHE314A)
Compound 1

2 H-Bonding(-O-CH3 & ASN291A)

(-(CO)-OCH3 & ASN291A)
Compound 2

2 H-Bonding(-SO2NH2 & ASN291A)

Compound 3 (-NH in the ring with LYS565A)
 5H-Bonding (-N-OH & GLU271A)
(-O-CH3 & LYS565A)
(-SO2NH2 & LYS565A)
(-SO2NH2 & LYS565A)
Compound 4 (-SO2NH2 & LYS565A)
Pi-Pi stacking with TYR383A
5 H-Bonding (-N-OH & GLY268A)
(-N-OH & GLY268A)
(-N-OH & GLY268A)
(-SO2NH2 &HIS295A)
Compound 5
(-SO2NH2 & GLU325A)
1 Pi-Pi stacking (TYR383A)
4 H-Bonding (-N-OH & GLY296A)
(-OSO2NH2 & ASN291A)
(-N-OH & GLU296A)
Compound 6 (-O-CH3 & LYS565A)
Charge interaction (-NH2 & GLU271A,GLU318A)
4 H-Bonding (-NH2 &GLY269A)
(-NH2 & GLU296A)
(-N-OH & TYR383A)
Compound 7 (-N-OH & TYR383A)
Charge interaction (GLU271A,GLU296A & NH2)
 Docking Result
COMPOUND DOCKING SCORE
1 -69.2399
2 16.2488
3 -74.7594
4 -71.4563
5 -64.7486
6 -47.6811
7 -69.8119
6-Gingerol -72.2882
Compound 4 Compound 5
POSSIBLE SYNTHETIC ROUTE
 POSSIBLE METABOLISM

Oxidation of ether group catalysed by Cyt P450

 Conclusion
◆ The synthesis of the new molecules is proposed.
◆ Docking studies revealed that the newly designed molecules showing better interactions
with the target protein compared to the 6-gingerol
◆ The possible metabolism of the active molecule is also discussed.
Thank You!