Republic of Iraq

Ministry of Higher Education

and Scientific Research
Al-Rasheed University College
Department of Pharmacy

Design New Molecule and Insilco Prediction of

Activity against Breast Cancer Targeted PAR

Graduation Project
Submitted to the Department of Pharmacy/ Al Rasheed University Collegein Partial
Fulfillment of the Requirement for the Degree of Bachelor in
Pharmacy

By
Athraa Qais Ibrahim
Teeba sadiq abd alrazaq
Al-Hassan anmar abd alameer

Supervised By
Assistant Lecturer Assistant Lecturer
HayderRaedFadhel Hawazin Aziz Hamim

2023 AD 1444 AH
 Dedication

We dedicate our graduation thesis to our country, Iraq

to our families ,

to the supervisors of our research

Dr Hayder Raed Fadhel

and

Dr Hawazin Aziz Hamim

who helped us complete our graduation thesis…

To everyone who supported us and helped us grow through the years .

I
 Acknowledgments

We would like to express our gratitude and appreciation to our

supervisors ,

Dr Hayder Raed Fadhel

and
Dr Hawazin Aziz Hamim

, for scientific guidance, valuable devices, help and encouragement

through the course of this work .

II
 Dedication I
Acknowledgment II
List of Contents III
List of Tables V
List of Schemes VI
List of Figures VI
List of Abbreviations VIII
Abstract IX

1.1. overview on cancer 1

1.2. Breast cancer 2
1.3. Type of Breast cancer 3
1.3.1. Hormone Receptor Positive breast cancer and their targeted 3
1.3.2. Triple Negative breast cancer 4
1.4. Poly adenosine diphosphate-ribose polymerase 5
1.5. Mechanism of action of PARP inhibitors 6
1.5.1 Drug available targeting PARP 6
1.6. Drug design strategy 7
1.6.1. Virtual screening (VS) 7
1.6.1.1 Structure-based drug design 8
1.6.1.2 Ligand-based drug design 10
1.7. Structure based drug design 10
1.7.1. Molecular Docking 11
1.8. Pharmacokinetics study of design compounds (ADME) 13
1.9. Rational design of our work 14

III
 2.1. Computational softwares 16
2.2. Characterizition 16
2.2.1. Topological descriptor 16
2.2.2. Partitioning coefficients 16
2.2.3. M.Wt 17
2.2.4. Acid-base properties (PKa) 17
2.3. Scheme of design 17
2.4. General Technique to design our final compounds 20
2.4.1. Step one 20
2.4.2. Step two 20
2.5. Computational Methods 20
2.5.1. ADME procedure 20
2.5.2. Ligand and protein receptor preparation 21
2.5.3.Docking procedure 21

3.1. Characterization of final compounds 22

3.2. Interpretation result of ADME procedure 24
3.3. Interpretation result of Docking procedure 34

IV
Table Title Page
2-1 Represent programs and their function in our work 16
2-2 Demonstrate different functional Groups 19
3-1 Reprepresent chemical structures of final compounds with 22
Molecular Formula & Molecular Weight
3-3 Binding energies for final compounds (2a-e),(3a-e),(4a-e), 24
olaparib and reference drug docked with PAPR-1
3-3 Binding energies for final compounds and olaparib and docked 34
with PAPR-1

V
Scheme Title Page

1-1 Design strategies 15

2-1 Represent the way to reach final compounds 18

Figure Title Page

1-1 Common type of Cancer 1
1-2 overview of carcinogenesis 2
1-3 Virtual Screening Steps 8
1-4 Overall steps of structure based drug design 9

1-6 Steps comparison between SBDD and LBDD 11

2-1 Computational protocol of the desired compounds 21

3-1 ADME study of compound (2a) 25

3-2 ADME study of compound (2b) 26
3-3 ADME study of compound (2c) 26
3-4 ADME study of compound (2d) 27
3-5 ADME study of compound (2e) 27
3-6 ADME study of compound (3a) 28
3-7 ADME study of compound (3b) 29
3-8 ADME study of compound (3c) 29

VI
3-9 ADME study of compound (3d) 30
3-10 ADME study of compound (3e) 30
3-11 ADME study of compound (4a) 30
3-12 ADME study of compound (4b) 31
3-13 ADME study of compound (4c) 32
3-14 ADME study of compound (4d) 32
3-15 ADME study of compound (4e) 33
3-16 Represent 2D and 3D shape with their interactions bond 35
of Compound (2b) with active site of PARP1 enzyme
3-17 Represent 2D and 3D shape with their interactions bond 35
of Compound (2c) with active site of PARP1 enzyme
3-18 Represent 2D and 3D shape with their interactions bond 36
of Compound (3a) with active site of PARP1 enzyme
3-19 Represent 2D and 3D shape with their interactions bond 36
of Compound (3b) with active site of PARP1 enzyme
3-20 Represent 2D and 3D shape with their interactions bond 37
of Compound (3c) with active site of PARP1 enzyme
3-21 Represent 2D and 3D shape with their interactions bond 37
of Compound (3d) with active site of PARP1 enzyme
3-22 Represent 2D and 3D shape with their interactions bond 38
of Compound (4e) with active site of PARP1 enzyme.
Figure (3-23): Represent 2D and 3D shape with their
interactions bond of reference drug (olaparib) with
active site of PARP1 enzyme
3-23 Represent 2D and 3D shape with their interactions bond 38
of reference drug (olaparib) with active site of PARP1
enzyme

VII
 # Abbreviation Explanation

2 ADME Absorption, Distribution, Metabolism and Excretion

7 BBB Blood brain barrier

8 BC Breast cancer
19 ER Estrogen receptor
20 ER+ Estrogen receptor positive
21 ER- Estrogen receptor negative
26 GOLD Genetic Optimization of Ligand Docking
27 HBA Hydrogen bond acceptor
28 HBD Hydrogen bond donator
46 PARP1 PARP1 poly(ADP-ribose) polymerase 1
56 TNBC Triple negative breast cancer

VIII
 Abstract
Breast cancer is one of the widely deadly diseases worldwide. Breast cancer is the most
common type of cancer in the UK. Most women diagnosed with breast cancer are over
the age of 50, but younger women can also get breast cancer. The standard treatment
choices for solid tumors are still chemotherapy method to kill cancer cell by interfering
with DNA and RNA synthesis. Chemotherapies, however are restricted by their non -
specific modes of action, with normal cells also affected during therapy. Eighty per cent
of all new BC cases diagnosed are in response to overexpression of estrogen receptors.
Within the spectrum of breast cancer, triple negative breast cancer is known as a type of
breast cancer in which there is a lack of expression of estrogen receptor, progesterone
receptor and Human Epidermal Growth Factor Receptor 2 and overexpress of PARPI.
To identify new potential targeted anti-breast cancer agents, three different series each
one contain five derivatives were design and evaluated Insilco for targeted PARP1
enzyme. Evaluation methods were used before synthesis using molecular docking via
Molecular Operating Environment (MOE) Suite software. Docking results exhibited
significant binding affinity of most compounds compared to Olaparib as a reference
drug. Also Structures pharmacokinetic prediction of final compounds were done. The
result of docking for compounds with higher energy score are (-8.72, -8.82, - 9.10, -
9.89, -9.32 and -8.71) for compound (2b, 3a, 3b, 3c, 3d and 4e) respectively, while than
Olaparib with energy score (-8.61). All final compounds shown high GIT absorption
except compound 3b.

IX