BINDING AFFINITY OF ANTI CANCEROUS COMPOUNDS IN

ABL1 PROTEIN

Guidance bySanjay Kumar

Programmer, Biotech Park , Lucknow

PRESENTED BY: S M SHAYEZ KARIMM.Sc. Bioinformatics

Central University of South Bihar

• 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

INTRODUCTION

• 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

Cont….

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

OBJECTIVE

• 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

ABOUT TARGET PROTEIN

Fig:- target protein http://www.rcsb.org/pdb/3UE4) `

• 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.

MATERIALS AND MATHEODS

• DatabasesPDB (http://www.rcsb.org/pdb/)Pubchem (https://pubchem.ncbi.nlm.nih.gov/)NCBI (http://www.ncbi.nlm.nih.gov/)

• SoftwareOpenbabel

ChimeraAutodockCygwin Ligplot

DATABASES & SOFTWARES

After docking we have selected top ten compound based on lowest binding free energy.

Table :- Top ten compound baised on lowest binding energy

RESULTS AND DISCUSSION

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

TABLE :- INTERACTION ENERGY MOLECULAR HYDROGEN BOND INTERACTIONS OF

INTERACTION ANALYSIS

S NO. COMPOUND AMINO ACID

NO OF HYDROG

EN

DISTANCE IN Å

AMINO ACID INTERACTED

1(A) BEXAROTENE ASN 2 2.78 ,2.98 GLY321,LEU370,VAL299,ALA380,ASP381,THR315,PHE382,MET290,LYS271,GLU286,ASN368,ARG367

2(B) ABIRATERONE ASP 1 2.88 ALA380,VAL299,LEU370,VAL256,GLY249,GLY250,PHE382,MET290

3(C) CYPROTERONE LYS 1 3.14 ILE313,PHE382,ARG367,ASN322,ASN368,LEU370,GLY321,VAL256,THR315

4(D) DAUNORUBICIN ASP 1 2.55 MET290,VAL299,PHE382,ALA380,ASP381,THR315,LEU370,ASN322,ARG367,ASN368

5(E) EXEMESTANE - - - MET290,PHE382,ALA380,ASP381,VAL299,ARG367,LEU370,VAL256,THR315,LYS271,ILE313

6(F) MEGESTROL THR, LYS 2 2.61,2.81 MET290,VAL299,LEU370,ALA380,ARG367,ASN368,GLN252,VAL256,PHE382,ILE313

7(G) CETUXIMAB LYS 1 3.71 ARG367,ASN368,LEU370,VAL299,MET318,THR315,VAL256,PHE382,GLN252

8(H) LAPATINIB ASP,PHE 2 3.10 ,3.24 ALA380,THR315,LEU370,ASN322,GLY321,VAL256,LYS271,VAL299,MET290

9(I) BICALUTAMIDE ARG,THR 2 2.67,3.23 VAL256,LEU248,GLY249,LEU370,MET290,LYS271,PHE382,ILE313,ALA380,VAL299,

10(J) ANASTROZOLE LYS 1 2.75 GLN252,ARG367,LEU370,ASN368,ALA380,PHE382,VAL256

Through Ligplot we analyze the top ten compound

• 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

Cont …

Fig:- interaction analysis of Megestrol

• 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

CONCLUSIONS

THANK YOU!!!