binding affinity of anti cancerous compound in ABL1 protein

1. Guidance by
Sanjay Kumar
Programmer, Biotech
Park , Lucknow
PRESENTED BY:
S M SHAYEZ KARIM
M.Sc. Bioinformatics
Central University of South Bihar

2. • Cancer is a disease characterized by uncontrollable,
irreversible, independent, autonomous, uncoordinated and
relatively unlimited and abnormal over growth of tissues.
• The abnormalities in cancer cells usually result from
mutations in protein-encoding genes that regulate cell division.
• More than 200 types of cancer have been identified . Like Anal
cancer, bladder cancer, breast cancer, prostate cancer, skin
cancer, lung cancer, liver cancer, leukemia .
• Leukemia :- it is cancer of the blood cells. In most cases the
cancer cells form a tumor. But some cancers, like leukemia,
rarely form tumors. Instead, these cancer cells are in the blood
and bone marrow.
• Chronic myeloid leukemia (CML) is caused by
the kinase activity of the BCR-Abl fusion protein

3. • CML is a clonal myeloproliferative neoplasm
• Fusion of 2 genes: BCR (or chromosome 22) and ABL1 (on chromosome
9), resulting in BCR-ABL1 fusion gene
• Final result: Abnormal chromosome 22 called Philadelphia (Ph)
chromosome
• Final product: BCR-ABL1 fusion protein, a dysregulated tyrosine kinase
• Uncontrolled production of mature and maturing granulocytes
• Predominantly neutrophils, but also basophils and eosinophils
• Chronic phase, accelerated phase, blast crisis

4.  To find the Anti-cancer compound in protein Tyrosine kinase
ABL1 protein by Docking study

5. • Abelson murine leukemia viral oncogene homolog 1
also known as ABL1 is a protein that, in humans, is
encoded by the ABL1 gene (previous symbol ABL)
located on chromosome 9.
• c-Abl is sometimes used to refer to the version of the
gene found within the mammalian genome, while v-
Abl refers to the viral gene.
• Mutations in the ABL1 gene are associated
with chronic myelogenous leukemia (CML). In CML,
the gene is activated by being translocated within
the BCR (breakpoint cluster region) gene on
chromosome 22. This new fusion gene, BCR-ABL,
encodes an unregulated, cytoplasm-targeted tyrosine
kinase that allows the cells to proliferate without being
regulated by cytokines. This, in turn, allows the cell to
become cancerous
Fig:- target protein
http://www.rcsb.org/pdb/3UE4)
`

6. • SELECTION OF TARGET PROTEIN:- The Protein we have selected is
ABL1 .
PDB ID :3UE4 PubMed ID:22493660
Length:287 Resolution (A°): 2.42
Molecule:Tyrosine-protein kinase ABL1
• SELECTION OF LIGAND:- We have collected 80 compounds (ligands)
from Pubchem. Those ligands which follow Lipinski's Rule of Five were
selected among several ligands found on the basis of drug similarity.

7. • Databases
PDB (http://www.rcsb.org/pdb/)
Pubchem (https://pubchem.ncbi.nlm.nih.gov/)
NCBI (http://www.ncbi.nlm.nih.gov/)
• Software
Openbabel
Chimera
Autodock
Cygwin
Ligplot

8.  After docking we have selected top ten compound based on
lowest binding free energy.
 Table :- Top ten compound baised on lowest binding energy
S NO. COMPOUND RUN Estimated Free Energy of
Binding (KCAL/MOL)
1 BEXAROTENE 9 -5.92
2 ABIRATERONE 3 -5.54
3 CYPROTERONE 5 -5.47
4 DAUNORUBICIN 6 -5.31
5 EXEMESTANE 4 -5.25
6 MEGESTROL 10 -5.18
7 CETUXIMAB 1 -5.12
8 LAPATINIB 7 -5.04
9 BICALUTAMIDE 8 -4.92
10 ANASTROZOLE 2 -4.83

9. TABLE :- INTERACTION ENERGY MOLECULAR HYDROGEN BOND INTERACTIONS OF
S NO. COMPOUND AMINO ACID NO OF
HYDROGE
N
DISTANCE IN
Å
AMINO ACID INTERACTED
1(A) BEXAROTENE ASN 2 2.78 ,2.98 GLY321,LEU370,VAL299,ALA380,ASP381,THR315,PH
E382,MET290,LYS271,GLU286,ASN368,ARG367
2(B) ABIRATERONE ASP 1 2.88 ALA380,VAL299,LEU370,VAL256,GLY249,GLY250,PH
E382,MET290
3(C) CYPROTERONE LYS 1 3.14 ILE313,PHE382,ARG367,ASN322,ASN368,LEU370,GLY
321,VAL256,THR315
4(D) DAUNORUBICIN ASP 1 2.55 MET290,VAL299,PHE382,ALA380,ASP381,THR315,LE
U370,ASN322,ARG367,ASN368
5(E) EXEMESTANE - - - MET290,PHE382,ALA380,ASP381,VAL299,ARG367,LE
U370,VAL256,THR315,LYS271,ILE313
6(F) MEGESTROL THR, LYS 2 2.61,2.81 MET290,VAL299,LEU370,ALA380,ARG367,ASN368,G
LN252,VAL256,PHE382,ILE313
7(G) CETUXIMAB LYS 1 3.71 ARG367,ASN368,LEU370,VAL299,MET318,THR315,V
AL256,PHE382,GLN252
8(H) LAPATINIB ASP,PHE 2 3.10 ,3.24 ALA380,THR315,LEU370,ASN322,GLY321,VAL256,LY
S271,VAL299,MET290
9(I) BICALUTAMIDE ARG,THR 2 2.67,3.23 VAL256,LEU248,GLY249,LEU370,MET290,LYS271,PH
E382,ILE313,ALA380,VAL299,
10(J) ANASTROZOLE LYS 1 2.75 GLN252,ARG367,LEU370,ASN368,ALA380,PHE382,VA
L256
Through Ligplot we analyze the top ten compound

10. • Among these ten compounds LIGAND_6 [Megestrol] was found to bind
with the target more efficiently than other compound with best dock score
Hence, LIGAND_6 has been emerged as a promising Anti-cancerous drug
candidate with potential effects
Fig:- interaction analysis of Megestrol

11. • From the comparative analysis of different parameters of all
ligands it can be concluded that Megestrol is the best ligand as
it has two Hydrogen bond Interaction, Interacting Residues
(Thr, Lys) the lowest Hydrogen bond Length distance in
angstrom (2.61, 2.81) respectively .
• From this project it can be concluded that Megestrol can be
used as drug against ABL1 protein for the pandemic spread of
the CML disease