Computer-Aided Design and Modeling of Protein Kinase Inhibitors
- Issued Date
- 2016
- Abstract
- Protein kinases are recognized as one of the best explored superfamilies in the human genome, which catalyze the transfer of terminal phosphate groups from ATP to the hydroxyl groups of specific amino acid residues. Protein kinases are the most intensively pursued drug targets due to their crucial roles in cellular signaling. Abnormal kinase activity is associated with various human diseases including cancer, arthritis, diabetes and cardiovascular disease. Protein kinase inhibitors are now well established as clinically useful drugs, predominantly for the cancer treatment. Pharmaceutical companies are conducting extensive research on kinases to develop novel therapeutic agents. The motivation of the present work in general was to expand the knowledge on the design of kinase targeting inhibitors, potentially suitable as therapeutic agents for the treatment of various cancers. This study attempts to attain it by means of rational molecular modeling approaches. Advanced drug design computational techniques were applied to design novel protein kinase inhibitors possessing potential anticancer activity. Several classes of protein kinase inhibitors including Chk1, PLK2, Mer kinase and JAK3 inhibitors were used in the project. 3D-QSAR, molecular docking and MD simulations are widely used techniques in the computer-aided drug design field. 3D-QSAR approaches were applied to determine the key structural elements that affect the inhibitory activity of a particular class of kinase inhibitors. CoMFA and CoMSIA models provided guidelines for the modification of kinase inhibitors to improve their potency. The structural requirements identified in the current study were utilized strategically in the successful designing of novel and highly potent kinase inhibitors. A preliminary in silico pharmacokinetic profile of the designed molecules showed promising results. The interactions between kinase and their inhibitors were further explored through docking and MD simulations. Molecular docking determined the binding modes of inhibitors in the active site of the kinase. MD simulations assisted in gaining deeper insights into the binding mechanism of the inhibitors. Overall, this integrated computational study aided in the design of new kinase inhibitors with improved potency. The research outcomes of this study could be further exploited to develop novel anticancer agents.
Keywords: Protein kinase, 3D-QSAR, Molecular docking, MD simulation
|단백질카이네이즈는 인간게놈에서 코딩 되어있는 가장 잘 알려진 슈퍼패밀리중의 하나이다. 이것은 단백질시료의 특정한 아미노잔기의 수산기 그룹에 ATP를 사용하여 phosphate기를 전달한다. 단백질 카이네이즈는 세포간의 신호전달에서의 특별한 역할 때문에 신약개발의 타깃으로서 대단히 많이 연구되어왔다. 비정상적인 카이네이즈의 작용은 암, 관절염, 비만, 그리고 심혈관계의 질환등의 다양한 인간의 질병과 관련되어 있다. 따라서, 많은 제약회사에서 새로운 치료제의 타겟으로써 카이네이즈에 대한 집중적인 연구가 진행되고 있다. 현재 본 연구에서는 카이네이즈를 타깃으로 하는 억제제를 설계하는 기법을 개발하고 항암제로 작동할 수 있는 유효물질을 찾아보는 것이 목표이다. 항암효능을 가진 새로운 카이에니즈 억제에를 디자인하기 위하여, 다양한 최신의 신약설계기법을 활용하였다.
Chk1, PLK2, Mer kinase, JAK3 등의 다양한 카이네이즈의 억제제들을 연구하였다. 연구방법으로는 3차원 QSAR을 이용하여 특정한 카이네이즈억제제 그룹의 억제효능에 영향을 미치는 인자들을 결정했다. CoMFA와 CoMSIA는 카이네이즈 억제들들의 효능을 증진시키는 가이드라인을 제시한다. 현재 연구에서 발견된 구조적인 특성들은 보다 나은 카이네이즈 억제제를 얻는데 중요하다. 이러한 카이네이즈와 억제제의 상호작용은 도킹과 MD 시뮬레이션을 통하여 더 자세히 연구되었다. 즉, 도킹을 통해서 카이네이즈의 활성자리에서 결합하는 모형을 얻을 수 있고, MD 시뮬레이션은 억제제들이 어떻게 결합하는지에 대한 보다 자세한 정보를 제공한다. 요약하면, 이러한 다양한 계산방법을 결합하면 보다 좋은 효능을 가진 새로운 카이네이즈억제제를 얻는데 가이드라인을 제공하며, 계산의 결과는 새로운 항암제를 찾는데 도움을 준다.
키워드: 단백질 카이네이즈, 3차원 QSAR, 분자 도킹, MD 시뮬레이션
- Alternative Title
- 단백질 키나제 억제제의 컴퓨터를 이용한 설계 및 모델링
- Alternative Author(s)
- Balupuri Anand
- Affiliation
- Department of Biomedical Sciences, Graduate School of Chosun University
- Department
- 일반대학원 의과학과
- Advisor
- Seung Joo Cho
- Awarded Date
- 2017-02
- Table Of Contents
- CONTENTS
Abbreviations……………………………………………….………...................iv
List of Tables………………………………………………………………..…...vi
List of Figures......................................................................................................vii
Abstract (English)……………………………………………………….……….x
Abstract (Korean)................................................................................................xii
PART I
General description of protein kinases ………………………….…………...1-4
1. The human kinome………………………………………………….……….…2
2. Structure of kinase domain………………………………………….………….3
3. Protein kinases as drug targets……………………………………….…………4
PART II
In silico design of novel Chk1 inhibitors as anticancer agents using a combined 3D-QSAR and molecular docking approach……………………5-39
1. Introduction…………………………………………………………………….6
2. Materials and methods…………………………………………………….……7
2.1. Data set……………………………………………………...……….7
2.2. Molecular modeling…………………………………………..........22
2.3. Molecular alignment………………………………………...……..22
2.4. CoMFA and CoMSIA interaction energies…………………..……23
2.5. PLS regression analysis……………………………………..……..24
2.6. Predictive correlation coefficient…………………………...……...24
2.7. Validation of the 3D-QSAR models………………………...……..25
2.8. Molecular docking…………………………………………...…….25
3. Results and discussion………………………………………………………...26
3.1. Series A…………………………………………………...………..26
3.1.1. Molecular docking…………………………….………..26
3.1.2. 3D-QSAR analysis……………………………….……..27
3.1.3. Contour maps…………………………………….……..29
3.2. Series B……………………………………………………...……..32
3.2.1. 3D-QSAR analysis…………………………….………..32
3.2.2. Contour maps…………………………………….……..33
3.2.3. Molecular docking…………………………….………..35
3.2.4. Designing of potent analogues………………….………37
4. Conclusion…………………………………………………………………….38
PART III
A computational strategy for the design of PLK2 inhibitors…………….40-61
1. Introduction…………………………………………………………………...41
2. Materials and methods………………………………….……………………..42
2.1. Data set……………………………………...……………………...42
2.2. 3D-QSAR analysis...…………………………….............................52
2.3. Molecular docking ………………………………...………………53
2.4. MD simulation ………………………………...….……………….53
3. Results and discussion………………………………………………………...54
3.1. 3D- QSAR analysis.…………………………...…………………...54
3.2. Contour analysis………………………………...………………….55
3.3. Molecular docking ………………………………...………………56
3.4. MD simulation …………………………...……….……………….58
4. Conclusion…………………………………………………………………….60
PART IV
Exploration of structural requirements of Mer kinase inhibitors through molecular modeling techniques ……………………………….………..….62-77
1. Introduction…………………………………………………………………...63
2. Materials and methods………………………………….……………………..63
2.1. Data set……………………………………...……………………...63
2.2. 3D-QSAR analysis...…………………………….............................70
2.3. Molecular docking ………………………………...………………71
2.4. MD simulation ………………………………...….……………….71
3. Results and discussion………………………………………………………...72
3.1. 3D-QSAR analysis.…………………………...…………….……...72
3.2. Contour analysis………………………………...………………….73
3.3. Molecular docking ………………………………...………………74
3.4. MD simulation …………………………...……….……………….75
4. Conclusion…………………………………………………………………….77
PART V
3D-QSAR assisted design and in silico ADMET prediction of novel JAK3 inhibitors…………………………………………………………………...78-131
1. Introduction…………………………………………………………………...79
2. Materials and methods………………………………….……………………..79
2.1. Data set……………………………………...……………………...79
2.2. 3D-QSAR analysis...…………………………….............................90
2.3. Molecular docking………………………………………..………..91
2.4. MD simulation……………………………………………………..91
3. Results and discussion………………………………………………………...91
3.1. 3D- QSAR analysis.…………………………...…………………...91
3.2. Contour analysis………………………………...………………….92
3.3. Molecular docking…………………………………………………95
3.4. MD simulation……………………………………………………..96
3.5. Design of new compounds…….…………………...………………98
4. Conclusion…………………………………………………………………...131
PART VI
Conclusion of the study……………………………………………..……132-133
Conclusions…………………………………………………………...………..133
REFERENCES………………...…………………………………………134-140
APPENDIX…………………………………………………………….....141-148
A. List of publications……………………………...…………………………..142
B. Acknowledgement…………………...……………………………………...146
- Degree
- Doctor
- Publisher
- Graduate School of Chosun University
- Citation
- 바루푸리 아난드. (2016). Computer-Aided Design and Modeling of Protein Kinase Inhibitors.
- Type
- Dissertation
- URI
- https://oak.chosun.ac.kr/handle/2020.oak/13001
http://chosun.dcollection.net/common/orgView/200000265869
- Appears in Collections:
- General Graduate School > 4. Theses(Ph.D)
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