Abstract
In our previous study, a protein engineering approach, accounting for the effects of single point mutations of the binding site residues on the stability of 22 thiazolo[4,5-d]pyrimidines in complex with the intracellular kinase domain of EGFR (PDB ID: 1XKK), was established in a systematic manner to be an efficient strategy for the identification of anti-EGFR-related-cancer drug candidates. The inhibitory activities of two lignad molecules, 4-(7-(3-chloro-4-morpholinophenylamino)thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide and 4-(7-(4-morpholinophenylamino) thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide, exhibited some sort of uniqueness. Regardless of a slight mutual structural difference between these two ligands in only a peripheral Cl atom, their inhibitory activities against EGFR appeared to be associated with two quite opposite structural bases respectively. Herein, the fundamental rationalization of the remarkable standpoint is elaborated using both molecular docking and molecular dynamics simulations. Consequently, a number of implications of vital importance for the successful structure-based design of prospective drugs against EGFR-related cancers are discussed.
Keywords: Cancer, drug design, EGFR, inhibitor, ligand, single point mutation, thiazolo pyrimidine, tyrosine kinase.
Medicinal Chemistry
Title:Structural Elucidation of Unique Inhibitory Activities of Two Thiazolo[ 4,5-d]pyrimidines Against Epidermal Growth Factor Receptor (EGFR): Implications for Successful Drug Design
Volume: 10 Issue: 1
Author(s): Petar M. Mitrasinovic
Affiliation:
Keywords: Cancer, drug design, EGFR, inhibitor, ligand, single point mutation, thiazolo pyrimidine, tyrosine kinase.
Abstract: In our previous study, a protein engineering approach, accounting for the effects of single point mutations of the binding site residues on the stability of 22 thiazolo[4,5-d]pyrimidines in complex with the intracellular kinase domain of EGFR (PDB ID: 1XKK), was established in a systematic manner to be an efficient strategy for the identification of anti-EGFR-related-cancer drug candidates. The inhibitory activities of two lignad molecules, 4-(7-(3-chloro-4-morpholinophenylamino)thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide and 4-(7-(4-morpholinophenylamino) thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide, exhibited some sort of uniqueness. Regardless of a slight mutual structural difference between these two ligands in only a peripheral Cl atom, their inhibitory activities against EGFR appeared to be associated with two quite opposite structural bases respectively. Herein, the fundamental rationalization of the remarkable standpoint is elaborated using both molecular docking and molecular dynamics simulations. Consequently, a number of implications of vital importance for the successful structure-based design of prospective drugs against EGFR-related cancers are discussed.
Export Options
About this article
Cite this article as:
Mitrasinovic M. Petar, Structural Elucidation of Unique Inhibitory Activities of Two Thiazolo[ 4,5-d]pyrimidines Against Epidermal Growth Factor Receptor (EGFR): Implications for Successful Drug Design, Medicinal Chemistry 2014; 10 (1) . https://dx.doi.org/10.2174/157340641001131226122124
DOI https://dx.doi.org/10.2174/157340641001131226122124 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
The Structure and Pharmacological Functions of Coumarins and Their Derivatives
Current Medicinal Chemistry Microglia NLRP3 Inflammasomes Activation Involving Diabetic Neuroinflammation in Diabetic Mice and BV2 Cells
Current Pharmaceutical Design Febrile Neutropenia in Children with Cancer: Approach to Diagnosis and Treatment
Current Pediatric Reviews Association of ATG7 Polymorphisms and Clear Cell Renal Cell Carcinoma Risk
Current Molecular Medicine Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target
Current Pharmaceutical Design Improving Safety of Gene Therapy
Current Drug Safety Antecedents of Voluntary Surgical Sterilization Among Poor Women in Tamil Nadu: Urban vs. Rural Areas
Current Women`s Health Reviews An Overview of Nanoformulated Nutraceuticals and their Therapeutic Approaches
Current Nutrition & Food Science Curcumin: A Natural Product for Diabetes and its Complications
Current Topics in Medicinal Chemistry The Neuroprotective Role of PEDF: Implication for the Therapy of Neurological Disorders
Current Molecular Medicine Curcumin: Structure-Activity Relationship Towards its Role as a Versatile Multi-Targeted Therapeutics
Mini-Reviews in Organic Chemistry MicroRNA-208a Potentiates Angiotensin II-triggered Cardiac Myoblasts Apoptosis via Inhibiting Nemo-like Kinase (NLK)
Current Pharmaceutical Design Antiangiogenic Therapy and Ovarian Cancer
Current Women`s Health Reviews Primary Immunodeficiency and Cancer in Children; A Review of the Literature
Current Pediatric Reviews Signs and Related Mechanisms of Ethanol Hepatotoxicity
Current Drug Abuse Reviews The Digenea Parasite Opisthorchis felineus: A Target for the Discovery and Development of Novel Drugs
Infectious Disorders - Drug Targets Nutraceuticals in Psychiatric Practice
Recent Patents on CNS Drug Discovery (Discontinued) Rikkunshito and Ghrelin Secretion
Current Pharmaceutical Design Testosterone Based Esters as Inhibitors of Aromatase (AR) and the use of the Substrate-Haem Complex Approach in the Rationalisation of the Inhibitory Activity of these Compounds
Letters in Drug Design & Discovery Multimodality Imaging of RNA Interference
Current Medicinal Chemistry