1st Edition
Anticancer Activity in Heterocyclic Organic Structures A Pathway to Novel Drug Development Part 1
This new volume in New Directions in Organic & Biological Chemistry, explores the development of cancer therapeutics, focusing on molecular chemistry and advanced drug design approaches. Written by experts in theoretical chemistry and molecular chemistry, they bridge the gap between theoretical chemistry, molecular biology, and drug development. In Part I, they focus on the fundamental properties of heterocyclic compounds and innovative methodologies being employed to enhance therapeutic potential. By exploring various classes of heterocyclic compounds and diverse anticancer mechanisms, this book provides a valuable resource for researchers, pharmaceutical scientists, and oncologists.
Key Features
- Provides an overview of computational approaches used in drug discovery, including molecular docking, QSAR, and virtual screening
- Focuses on the theoretical and practical aspects of these techniques, with applications across various therapeutic areas, including cancer
- Addresses the challenges in translating scientific research into effective treatments, offering insights into overcoming common obstacles in the development process
- These compounds represent a significant opportunity for the pharmaceutical industry to provide more effective and tailored cancer treatments, further driving market growth
- The breadth of the market for heterocyclic anticancer agents is vast and continues to expand as scientific advancements uncover new therapeutic targets
Aknewlegment ii
Author Biography. iii
List of figure. viii
Chapter 01 : Cancers and Anticancer Drugs 6
2. Mechanisms of carcinogenesis 7
3. Characteristics of the cancer cell 8
2. Classification of anticancer agents according to their mechanism of action. 10
2.1. Drugs with a direct action on DNA. 10
a) Alkylating agents and derivatives 10
2.2. Drugs with an indirect action on DNA. 12
a) Topoisomerase I and II inhibitors 12
2.4. Drugs targeting a specific receptor or mechanism in the tumor: Targeted therapy. 16
b) Tyrosine kinase inhibitors (TKI) 20
c) Serine/threonine kinase inhibitors (STKI) 21
2.5. Drugs targeting certain hormones: Hormone therapy. 24
a) Hormone therapy for breast cancer. 25
b) Hormone therapy for prostate cancer. 27
2.6. Drugs targeting the immune system: Immunotherapy 29
Chapter 02: In Silico Methods Used in the Design of New Anticancer Agents 34
II.... Discovery of New Drugs 35
1. Development of tailor-made molecules 35
2. Identification and validation of targets 36
3. Generation of Hits and Leads 36
5. Clinical trials and commercialization. 37
III.. In Silico Screening Methods 38
1. Structure-based screening methods 39
2. Ligand-based screening methods « ligand-based ». 39
1. Administration and absorption. 40
3. Lead-like selection criteria. 42
5. Metabolism and excretion 43
V.... Quantitative Structure-Activity Relationship (QSAR) Study. 44
1. QSAR Tools and Methodology. 47
1.1. Biological parameters. 47
1.2. Molecular descriptors. 48
2. Descriptor selection and reduction. 53
a) Principal Component Analysis (PCA) 54
b) Multiple Linear Regression. 54
d) Artificial Neural Networks (ANN) 55
c) Variance Inflation Factor (VIF) 59
d) Internal validation or cross-validation. 59
5. Creation of training and test datasets 63
6. Global strategy for QSAR studies 63
1. Comparative Molecular Field Analysis (CoMFA) 65
2. Comparative Molecular Similarity Index Analysis (CoMSIA) 66
4. Calculation of molecular interaction fields in both CoMFA and CoMSIA.. 66
5. Graphical visualization of models 68
6. Prediction and extrapolation. 69
3. Ligand-receptor interaction. 71
3.4. Cation-π interactions. 72
3.6. Van der Waals interactions. 73
4.1. Preparation and selection of receptors. 73
4.2. Main docking software. 74
5. Evaluation of docking methods 75
5.2. Root Mean Square Deviation (RMSD) 75
Application 1: QSAR Study of New Compounds Based on 1, 2, 4-triazole as Potential Anticancer Agents 86
II.... Material and Methods 88
2. Calculation of molecular descriptors. 90
III.. Results and Discussion. 92
1. Principal Components Analysis (PCA) 92
2. Multiple linear regressions (MLR) 96
3. Multiple nonlinear regressions (MNLR) 96
5. Artificial Neural networks (ANN) 98
IV.. Conclusion. 100
V.... References 101
Application 2 :3D-QSAR Study of the Chalcone Derivatives as Anti-cancer Agents 108
II.... Materials and Methods 111
2. Data set 111
5. CoMFA and CoMSIA studies 114
6. Partial least square analysis 114
7. Validation of the models 114
9. Model acceptability criteria. 115
10. Lipinski’s Rule and ADMET Prediction. 115
III.. Results and Discussion. 116
1. CoMFA statistical results 116
2. CoMSIA Statistical Results 116
3. Analysis of CoMFA and CoMSIA contour maps 119
5. Design for new chalcone as anticancer agents 124
6. Lipinski’s Rule and ADMET Prediction. 126
IV.. Conclusion. 127
V.... References 130
II.... Material and Methods 134
1.1. Data set 134
2. CoMFA and CoMSIA studies 138
3. Partial least square analysis 138
4. Validation of the models 139
6. Model acceptability criteria. 139
7. Drug Likeness and ADMET Prediction. 140
8. Molecular Docking Study. 140
III.. Results and discussion. 140
2. CoMFA statistical results 141
3. CoMSIA Statistical Results 141
6. Design for new Pyrazole as anticancer agents 148
9. Molecular docking study. 154
IV.. Conclusion. 156
V.... References 157
II.... Material and Methods 165
1.1. Ligands 165
1.2. Receptor 165
3. Docking validation protocol 167
III.. Results and Discussion. 168
2. Docking validation protocol 172
V.... References 174
General Conclusion. 175
Biography
Dr. Larbi EL Mchichi holds a PhD in Chemistry with a specialization in Theoretical Chemistry from Moulay Ismail University (Faculty of Sciences, Meknes). His doctoral research focused on the anticancer activity of heterocyclic organic molecules, using statistical and quantum methods, including QSAR modeling and molecular docking.
In his research, Dr. EL Mchichi explores innovative computational approaches to the design of novel therapeutic agents, particularly anticancer compounds, utilizing techniques like 3D-QSAR, drug-likeness assessment, ADMET prediction, and molecular docking simulations.
In addition to his research, he is a first-grade certified teacher of physics and chemistry at the secondary education level, where he strives to inspire his students with a passion for science and research.
Dr. EL Mchichi has authored several peer-reviewed publications in international journals, including work on the design of pyrazole derivatives as anticancer agents and the discovery of a new isatin scaffold for BCR-ABL tyrosine kinase inhibitors.
His research aims to contribute to the advancement of cutting-edge cancer therapies through the integration of computational methods and pharmaceutical science.
